Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use

ABSTRACT

Provided are compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, Z 1 , Z 2 , Z 3 , Z 4  and m are as defined herein. 
     Also provided is a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof. 
     Also provided are methods of using a compound of Formula I, or a pharmaceutically acceptable salt thereof.

This application claims the benefit of U.S. Provisional Application Nos.61/327,538, filed Apr. 23, 2010, 61/327,597, filed Apr. 23, 2010,61/412,299, filed Nov. 10, 2010, and 61/412,302, filed Nov. 10, 2010,each of which is incorporated by reference in its entirety for allpurposes.

The cytoskeleton of skeletal and cardiac muscle cells is unique comparedto that of all other cells. It consists of a nearly crystalline array ofclosely packed cytoskeletal proteins called the sarcomere. The sarcomereis elegantly organized as an interdigitating array of thin and thickfilaments. The thick filaments are composed of myosin, the motor proteinresponsible for transducing the chemical energy of ATP hydrolysis intoforce and directed movement. The thin filaments are composed of actinmonomers arranged in a helical array. There are four regulatory proteinsbound to the actin filaments, which allows the contraction to bemodulated by calcium ions. An influx of intracellular calcium initiatesmuscle contraction; thick and thin filaments slide past each otherdriven by repetitive interactions of the myosin motor domains with thethin actin filaments.

Of the thirteen distinct classes of myosin in human cells, the myosin-IIclass is responsible for contraction of skeletal, cardiac, and smoothmuscle. This class of myosin is significantly different in amino acidcomposition and in overall structure from myosin in the other twelvedistinct classes. Myosin-II forms homo-dimers resulting in two globularhead domains linked together by a long alpha-helical coiled-coiled tailto form the core of the sarcomere's thick filament. The globular headshave a catalytic domain where the actin binding and ATPase functions ofmyosin take place. Once bound to an actin filament, the release ofphosphate (cf. ADP-Pi to ADP) signals a change in structuralconformation of the catalytic domain that in turn alters the orientationof the light-chain binding lever arm domain that extends from theglobular head; this movement is termed the powerstroke. This change inorientation of the myosin head in relationship to actin causes the thickfilament of which it is a part to move with respect to the thin actinfilament to which it is bound. Un-binding of the globular head from theactin filament (Ca²⁺ regulated) coupled with return of the catalyticdomain and light chain to their starting conformation/orientationcompletes the catalytic cycle, responsible for intracellular movementand muscle contraction.

Tropomyosin and troponin mediate the calcium effect on the interactionon actin and myosin. The troponin complex is comprised of threepolypeptide chains: troponin C, which binds calcium ions; troponin I,which binds to actin; and troponin T, which binds to tropomyosin. Theskeletal troponin-tropomyosin complex regulates the myosin binding sitesextending over several actin units at once.

Troponin, a complex of the three polypeptides described above, is anaccessory protein that is closely associated with actin filaments invertebrate muscle. The troponin complex acts in conjunction with themuscle form of tropomyosin to mediate the Ca²⁺ dependency of myosinATPase activity and thereby regulate muscle contraction. The troponinpolypeptides T, I, and C, are named for their tropomyosin binding,inhibitory, and calcium binding activities, respectively. Troponin Tbinds to tropomyosin and is believed to be responsible for positioningthe troponin complex on the muscle thin filament. Troponin I binds toactin, and the complex formed by troponins I and T, and tropomyosininhibits the interaction of actin and myosin. Skeletal troponin C iscapable of binding up to four calcium molecules. Studies suggest thatwhen the level of calcium in the muscle is raised, troponin C exposes abinding site for troponin I, recruiting it away from actin. This causesthe tropomyosin molecule to shift its position as well, thereby exposingthe myosin binding sites on actin and stimulating myosin ATPaseactivity.

Human skeletal muscle is composed of different types of contractilefibers, classified by their myosin type and termed either slow or fastfibers. Table 1 summarizes the different proteins that make up thesetypes of muscle.

TABLE 1 Muscle Fiber Type Fast skeletal Slow Skeletal Myosin Heavy IIa,(IIb*), IIx/d Cardiac β Chain Troponin I (TnI) TnI fast SK TnI slow SKTroponin T TnT fast SK TnT slow SK (TnT) Troponin C TnC fast SK TnCslow/cardiac (TnC) Tropomyosin TM-β/TM-α/TPM 3 TM-β/TM-αs *MHC IIb isnot expressed in human muscle but is present in rodents and othermammals.

In healthy humans most skeletal muscles are composed of both fast andslow fibers, although the proportions of each vary with muscle type.Slow skeletal fibers, often called type I fibers, have more structuralsimilarity with cardiac muscle and tend to be used more for fine andpostural control. They usually have a greater oxidative capacity and aremore resistant to fatigue with continued use. Fast skeletal musclefibers, often called type II fibers, are classified into fast oxidative(IIa) and fast glycolytic (type IIx/d) fibers. While these muscle fibershave different myosin types, they share many components including thetroponin and tropomyosin regulatory proteins. Fast skeletal musclefibers tend to exert greater force but fatigue faster than slow skeletalmuscle fibers and are functionally useful for acute, large scalemovements such as rising from a chair or correcting falls.

Muscle contraction and force generation is controlled through nervousstimulation by innervating motor neurons. Each motor neuron mayinnervate many (approximately 100-380) muscle fibers as a contractilewhole, termed a motor unit. When a muscle is required to contract, motorneurons send stimuli as nerve impulses (action potentials) from thebrain stem or spinal cord to each fiber within the motor unit. Thecontact region between nerve and muscle fibers is a specialized synapsecalled the neuromuscular junction (NMJ). Here, membrane depolarizingaction potentials in the nerve are translated into an impulse in themuscle fiber through release of the neurotransmitter acetylcholine(ACh). ACh triggers a second action potential in the muscle that spreadsrapidly along the fiber and into invaginations in the membrane, termedt-tubules. T-tubules are physically connected to Ca2+ stores within thesarcoplasmic reticulum (SR) of muscle via the dihydropyridine receptor(DHPR). Stimulation of the DHPR activates a second Ca2+ channel in theSR, the ryanodine receptor, to trigger the release of Ca2+ from storesin the SR to the muscle cytoplasm where it can interact with thetroponin complex to initiate muscle contraction. If muscle stimulationstops, calcium is rapidly taken back up into the SR through the ATPdependent Ca2+ pump, SERCA.

Muscle function can become compromised in disease by many mechanisms.Examples include the frailty associated with old age (termed sarcopenia)and cachexia syndromes associated with diseases such as cancer, heartfailure, chronic obstructive pulmonary disease (COPD), and chronickidney disease/dialysis. Severe muscular dysfunction can arise fromneuromuscular diseases (such as Amyotrophic Lateral Sclerosis (ALS),spinal muscular atrophy (SMA) and myasthenia gravis) or muscularmyopathies (such as muscular dystrophies). Additionally, muscle functionmay become compromised due to rehabilitation-related deficits, such asthose associated with recovery from surgery (e.g. post-surgical muscleweakness), prolonged bed rest, or stroke rehabilitation. Additionalexamples of diseases or conditions where muscle function becomescompromised include peripheral vascular disease (e.g., claudication),chronic fatigue syndrome, metabolic syndrome, and obesity.

Accordingly, there is a need for the development of new compounds thatmodulate skeletal muscle contractility. There remains a need for agentsthat exploit new mechanisms of action and which may have better outcomesin terms of relief of symptoms, safety, and patient mortality, bothshort-term and long-term and an improved therapeutic index.

Provided is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R², R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, X, Z¹, Z², Z³, Z⁴ and m are as defined herein.

Also provided is a pharmaceutically acceptable composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof.

Also provided are methods for treating a disease or condition responsiveto modulation of the contractility of the skeletal sarcomere, forexample, modulation of the troponin complex of the fast skeletal musclesarcomere through one or more of fast skeletal myosin, actin,tropomyosin, troponin C, troponin I, and troponin T, and fragments andisoforms thereof.

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

Throughout this application, unless the context indicates otherwise,references to a compound of Formula I includes all subgroups of FormulaI defined herein, including all substructures, subgenera, preferences,embodiments, examples and particular compounds defined and/or describedherein.

References to a compound of Formula I and subgroups thereof includeionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates,co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides,S-oxides), esters, prodrugs, isotopes and/or protected forms thereof.“Crystalline form,” “polymorph,” and “novel form” may be usedinterchangeably herein, and are meant to include all crystalline andamorphous forms of the compound, including, for example, polymorphs,pseudopolymorphs, solvates (including hydrates), co-crystals, unsolvatedpolymorphs (including anhydrates), conformational polymorphs, andamorphous forms, as well as mixtures thereof, unless a particularcrystalline or amorphous form is referred to. In some embodiments,references to a compound of Formula I and subgroups thereof includepolymorphs, solvates, co-crystals, isomers, tautomers and/or oxidesthereof. In some embodiments, references to a compound of Formula I andsubgroups thereof include polymorphs, solvates, and/or co-crystalsthereof. In some embodiments, references to a compound of Formula I andsubgroups thereof include isomers, tautomers and/or oxides thereof. Insome embodiments, references to a compound of Formula I and subgroupsthereof include solvates thereof. Similarly, the term “salts” includessolvates of salts of compounds.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined herein. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible, and/or inherentlyunstable.

When a range of values is given (e.g., C₁₋₆ alkyl), each value withinthe range as well as all intervening ranges are included. For example,“C₁₋₆ alkyl” includes C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₂₋₆, C₃₋₆, C₄₋₆,C₅₋₆, C₁₋₅, C₂₋₅, C₃₋₅, C₄₋₅, C₁₋₄, C₂₋₄, C₃₋₄, C₁₋₃, C₂₋₃, and C₁₋₂alkyl.

When a moiety is defined as being optionally substituted, it may besubstituted as itself or as part of another moiety. For example, ifR^(x) is defined as “C₁₋₆ alkyl or OC₁₋₆ alkyl, wherein C₁₋₆ alkyl isoptionally substituted with halogen”, then both the C₁₋₆ alkyl groupalone and the C₁₋₆ alkyl that makes up part of the OC₁₋₆ alkyl group maybe substituted with halogen.

“Alkyl” encompasses straight and branched carbon chains having theindicated number of carbon atoms, for example, from 1 to 20 carbonatoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C₁₋₆alkyl encompasses both straight and branched chain alkyl of from 1 to 6carbon atoms. When an alkyl residue having a specific number of carbonsis named, all branched and straight chain versions having that number ofcarbons are intended to be encompassed; thus, for example, “propyl”includes n-propyl and isopropyl; and “butyl” includes n-butyl,sec-butyl, isobutyl and t-butyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl,hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. “Lower alkyl” refers toalkyl groups having 1 to 6 carbons.

“Haloalkyl” includes straight and branched carbon chains having theindicated number of carbon atoms (e.g., 1 to 6 carbon atoms) substitutedwith at least one halogen atom. In instances wherein the haloalkyl groupcontains more than one halogen atom, the halogens may be the same (e.g.,dichloromethyl) or different (e.g., chlorofluoromethyl). Examples ofhaloalkyl groups include, but are not limited to, chloromethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-chloroethyl,2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dichloroethyl,pentachloroethyl, and pentafluoroethyl.

“Alkenyl” refers to an unsaturated branched or straight-chain alkylgroup having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to6 carbon atoms) and at least one carbon-carbon double bond derived bythe removal of one molecule of hydrogen from adjacent carbon atoms ofthe corresponding alkyl. The group may be in either the cis or transconfiguration (Z or E configuration) about the double bond(s). Alkenylgroups include, but are not limited to, ethenyl, propenyl (e.g.,prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl),and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl). “Lower alkenyl” refers toalkenyl groups having 2 to 6 carbons.

“Alkynyl” refers to an unsaturated branched or straight-chain alkylgroup having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to6 carbon atoms) and at least one carbon-carbon triple bond derived bythe removal of two molecules of hydrogen from adjacent carbon atoms ofthe corresponding alkyl. Alkynyl groups include, but are not limited to,ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl(e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl). “Lower alkynyl”refers to alkynyl groups having 2 to 6 carbons.

“Cycloalkyl” indicates a non-aromatic, fully saturated carbocyclic ringhaving the indicated number of carbon atoms, for example, 3 to 10, or 3to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclicor polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl andcyclohexyl, as well as bridged and caged ring groups (e.g., norbornane,bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkylgroup may be aromatic, provided the polycyclic cycloalkyl group is boundto the parent structure via a non-aromatic carbon. For example, a1,2,3,4-tetrahydronaphthalen-1-yl group (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is a cycloalkylgroup, while 1,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety isbound to the parent structure via an aromatic carbon atom) is notconsidered a cycloalkyl group. Examples of polycyclic cycloalkyl groupsconsisting of a cycloalkyl group fused to an aromatic ring are describedbelow.

“Cycloalkenyl” indicates a non-aromatic carbocyclic ring, containing theindicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6ring carbon atoms) and at least one carbon-carbon double bond derived bythe removal of one molecule of hydrogen from adjacent carbon atoms ofthe corresponding cycloalkyl. Cycloalkenyl groups may be monocyclic orpolycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groupsinclude cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl,and cyclohexenyl, as well as bridged and caged ring groups (e.g.,bicyclo[2.2.2]octene). In addition, one ring of a polycycliccycloalkenyl group may be aromatic, provided the polycyclic alkenylgroup is bound to the parent structure via a non-aromatic carbon atom.For example, inden-1-yl (wherein the moiety is bound to the parentstructure via a non-aromatic carbon atom) is considered a cycloalkenylgroup, while inden-4-yl (wherein the moiety is bound to the parentstructure via an aromatic carbon atom) is not considered a cycloalkenylgroup. Examples of polycyclic cycloalkenyl groups consisting of acycloalkenyl group fused to an aromatic ring are described below.

“Aryl” indicates an aromatic carbon ring having the indicated number ofcarbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. Aryl groupsmay be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In someinstances, both rings of a polycyclic aryl group are aromatic (e.g.,naphthyl). In other instances, polycyclic aryl groups may include anon-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl) fused to an aromatic ring, provided the polycyclicaryl group is bound to the parent structure via an atom in the aromaticring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (wherein themoiety is bound to the parent structure via an aromatic carbon atom) isconsidered an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl(wherein the moiety is bound to the parent structure via a non-aromaticcarbon atom) is not considered an aryl group. Similarly, a1,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound tothe parent structure via an aromatic carbon atom) is considered an arylgroup, while 1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moietyis bound to the parent structure via a non-aromatic nitrogen atom) isnot considered an aryl group. However, the term “aryl” does notencompass or overlap with “heteroaryl”, as defined herein, regardless ofthe point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl areheteroaryl groups). In some instances, aryl is phenyl or naphthyl. Incertain instances, aryl is phenyl. Additional examples of aryl groupscomprising an aromatic carbon ring fused to a non-aromatic ring aredescribed below.

“Aralkyl” refers to a residue having the indicated number of carbonatoms (e.g., 7 to 12 or 7 to 10 carbon atoms) in which an aryl moiety isattached to the parent structure via an alkyl residue. The alkyl residuemay be straight-chain or branched. Examples include benzyl, phenethyland 1-phenylethyl.

“Heteroaryl” indicates an aromatic ring containing the indicated numberof atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of oneor more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, Oand S and with the remaining ring atoms being carbon. Heteroaryl groupsdo not contain adjacent S and O atoms. In some embodiments, the totalnumber of S and O atoms in the heteroaryl group is not more than 2. Insome embodiments, the total number of S and O atoms in the heteroarylgroup is not more than 1. Unless otherwise indicated, heteroaryl groupsmay be bound to the parent structure by a carbon or nitrogen atom, asvalency permits. For example, “pyridyl” includes 2-pyridyl, 3-pyridyland 4-pyridyl groups, and “pyrrolyl” includes 1-pyrrolyl, 2-pyrrolyl and3-pyrrolyl groups. When nitrogen is present in a heteroaryl ring, itmay, where the nature of the adjacent atoms and groups permits, exist inan oxidized state (i.e., N⁺—O⁻). Additionally, when sulfur is present ina heteroaryl ring, it may, where the nature of the adjacent atoms andgroups permits, exist in an oxidized state (i.e., S⁺—O⁻ or SO₂).Heteroaryl groups may be monocyclic or polycyclic (e.g., bicyclic,tricyclic).

In some instances, a heteroaryl group is monocyclic. Examples includepyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole,1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole,oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole),thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine,pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

In some instances, both rings of a polycyclic heteroaryl group arearomatic. Examples include indole, isoindole, indazole, benzoimidazole,benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole,benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole,1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine,3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine,1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine,1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine,3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine,1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine,1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine,furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine,[1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine,oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine,[1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine,oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine,[1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine,oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine,[1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine,thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine,[1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine,thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine,[1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine,thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine,[1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine,thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine,[1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline,quinazoline, quinoxaline, phthalazine, naphthyridine (e.g.,1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine,1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine),imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole,1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

In other instances, polycyclic heteroaryl groups may include anon-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclicheteroaryl group is bound to the parent structure via an atom in thearomatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylgroup (wherein the moiety is bound to the parent structure via anaromatic carbon atom) is considered a heteroaryl group, while4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound tothe parent structure via a non-aromatic carbon atom) is not considered aheteroaryl group. Examples of polycyclic heteroaryl groups consisting ofa heteroaryl ring fused to a non-aromatic ring are described below.

“Heterocycloalkyl” indicates a non-aromatic, fully saturated ring havingthe indicated number of atoms (e.g., 3 to 10, or 3 to 7, memberedheterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4heteroatoms) selected from N, O and S and with the remaining ring atomsbeing carbon. Heterocycloalkyl groups may be monocyclic or polycyclic(e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups includeoxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl andthiomorpholinyl. When nitrogen is present in a heterocycloalkyl ring, itmay, where the nature of the adjacent atoms and groups permits, exist inan oxidized state (i.e., N⁺—O⁻). Examples include piperidinyl N-oxideand morpholinyl-N-oxide. Additionally, when sulfur is present in aheterocycloalkyl ring, it may, where the nature of the adjacent atomsand groups permits, exist in an oxidized state (i.e., S⁺—O⁻ or —SO₂—).Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.In addition, one ring of a polycyclic heterocycloalkyl group may bearomatic (e.g., aryl or heteroaryl), provided the polycyclicheterocycloalkyl group is bound to the parent structure via anon-aromatic carbon or nitrogen atom. For example, a1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moiety is bound tothe parent structure via a non-aromatic nitrogen atom) is considered aheterocycloalkyl group, while 1,2,3,4-tetrahydroquinolin-8-yl group(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a heterocycloalkyl group. Examples ofpolycyclic heterocycloalkyl groups consisting of a heterocycloalkylgroup fused to an aromatic ring are described below.

“Heterocycloalkenyl” indicates a non-aromatic ring having the indicatednumber of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl)made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms)selected from N, O and S and with the remaining ring atoms being carbon,and at least one double bond derived by the removal of one molecule ofhydrogen from adjacent carbon atoms, adjacent nitrogen atoms, oradjacent carbon and nitrogen atoms of the correspondingheterocycloalkyl. Heterocycloalkenyl groups may be monocyclic orpolycyclic (e.g., bicyclic, tricyclic). When nitrogen is present in aheterocycloalkenyl ring, it may, where the nature of the adjacent atomsand groups permits, exist in an oxidized state (i.e., N⁺—O⁻).Additionally, when sulfur is present in a heterocycloalkenyl ring, itmay, where the nature of the adjacent atoms and groups permits, exist inan oxidized state (i.e., S⁺—O⁻ or SO₂—). Examples of heterocycloalkenylgroups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl,2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl,2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl,2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g.,2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl,dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl),tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl,1,2,3,6-tetrahydropyridinyl) and dihydropyridine (e.g.,1,2-dihydropyridine, 1,4-dihydropyridine). In addition, one ring of apolycyclic heterocycloalkenyl group may be aromatic (e.g., aryl orheteroaryl), provided the polycyclic heterocycloalkenyl group is boundto the parent structure via a non-aromatic carbon or nitrogen atom. Forexample, a 1,2-dihydroquinolin-1-yl group (wherein the moiety is boundto the parent structure via a non-aromatic nitrogen atom) is considereda heterocycloalkenyl group, while 1,2-dihydroquinolin-8-yl group(wherein the moiety is bound to the parent structure via an aromaticcarbon atom) is not considered a heterocycloalkenyl group. Examples ofpolycyclic heterocycloalkenyl groups consisting of a heterocycloalkenylgroup fused to an aromatic ring are described below.

Examples of polycyclic rings consisting of an aromatic ring (e.g., arylor heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl,2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl,benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl,indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl,2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl,1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl,2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl,2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl,1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl,2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl,4,5,6,7-tetrahydrobenzo[d]thiazolyl,5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl,4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one,indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one,1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one,benzofuran-3(2H)-one, isobenzofuran-1(3H)-one,benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one,benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one,benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one,benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one,benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one,1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one,quinazolin-4(3H)-one, quinazoline-2,4(1H,3H)-dione,quinoxalin-2(1H)-one, quinoxaline-2,3(1H,4H)-dione, cinnolin-4(3H)-one,pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one,pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one,1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one,1H-pyrrolo[2,3-b]pyridin-2(3H)-one,1,2-dihydropyrazolo[3,4-d]thiazol-3-one and4,5-dihydropyrrolo[3,4-d]thiazol-6-one. As discussed herein, whethereach ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl or heterocycloalkenyl group is determined by the atomthrough which the moiety is bound to the parent structure.

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are stereoisomers that arenon-superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The symbol “(±)” may be used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. A “meso compound” or “meso isomer” is anon-optically active member of a set of stereoisomers. Meso isomerscontain two or more stereocenters but are not chiral (i.e., a plane ofsymmetry exists within the molecule). The absolute stereochemistry isspecified according to the Cahn-Ingold-Prelog R-S system. When acompound is a pure enantiomer the stereochemistry at each chiral carboncan be specified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdisclosed and/or described herein contain one or more asymmetric centersand can thus give rise to enantiomers, diastereomers, meso isomers andother stereoisomeric forms. Unless otherwise indicated, compoundsdisclosed and/or described herein include all such possible enantiomers,diastereomers, meso isomers and other stereoisomeric forms, includingracemic mixtures, optically pure forms and intermediate mixtures.Enantiomers, diastereomers, meso isomers and other stereoisomeric formscan be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. Unless specified otherwise, when thecompounds disclosed and/or described herein contain olefinic doublebonds or other centers of geometric asymmetry, it is intended that thecompounds include both E and Z isomers.

The stereochemistry depicted in the structures of cyclic meso compoundsis not absolute; rather the stereochemistry is intended to indicate thepositioning of the substituents relative to one another, e.g., cis ortrans. For example,

is intended to designate a compound wherein the fluorine and pyridylsubstituents on the cyclobutyl ring are in a cis configuration to oneanother, while

is intended to designate a compound wherein the fluorine and pyridylsubstituents on the cyclobutyl ring are in a trans configuration to oneanother.

When a compound can exist as one or more meso isomers, all possible mesoisomers are intended to be included. For example, the compound5-bromo-3-fluoro-N-((3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridin-2-amineis intended to include both cis and trans meso isomers:

and mixtures thereof. Unless otherwise indicated, compounds disclosedand/or described herein include all possible meso isomers and mixturesthereof.

“Tautomers” are structurally distinct isomers that interconvert bytautomerization. Tautomerization is a form of isomerization and includesprototropic or proton-shift tautomerization, which is considered asubset of acid-base chemistry. Prototropic tautomerization orproton-shift tautomerization involves the migration of a protonaccompanied by changes in bond order, often the interchange of a singlebond with an adjacent double bond. Where tautomerization is possible(e.g. in solution), a chemical equilibrium of tautomers can be reached.An example of tautomerization is keto-enol tautomerization. A specificexample of keto-enol tautomerization is the interconverision ofpentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Anotherexample of tautomerization is phenol-keto tautomerization. A specificexample of phenol-keto tautomerization is the interconversion ofpyridin-4-ol and pyridin-4(1H)-one tautomers. When the compoundsdescribed herein contain moieties capable of tautomerization, and unlessspecified otherwise, it is intended that the compounds include allpossible tautomers.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, i.e., a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite, and such that the group can readily be removed after the selectivereaction is complete. A variety of protecting groups are disclosed, forexample, in T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999). Forexample, a “hydroxy protected form” contains at least one hydroxy groupprotected with a hydroxy protecting group. Likewise, amines and otherreactive groups may similarly be protected.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds describedherein and are not biologically or otherwise undesirable. Examples ofpharmaceutically acceptable salts can be found in Berge et al.,Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1),1-19. In many cases, the compounds described herein are capable offorming acid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. Pharmaceutically acceptableacid addition salts can be formed with inorganic acids and organicacids. Inorganic acids from which salts can be derived include, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, and phosphoric acid. Organic acids from which salts can be derivedinclude, for example, acetic acid, propionic acid, glycolic acid,pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonicacid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acidand salicylic acid. Pharmaceutically acceptable base addition salts canbe formed with inorganic and organic bases. Inorganic bases from whichsalts can be derived include, for example, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines; substituted aminesincluding naturally occurring substituted amines; cyclic amines; andbasic ion exchange resins. Examples of organic bases includeisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In some embodiments, thepharmaceutically acceptable base addition salt is chosen from ammonium,potassium, sodium, calcium, and magnesium salts.

If the compound described herein is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the compound is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds (see,e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences,January 1977, 66(1), 1-19). Those skilled in the art will recognizevarious synthetic methodologies that may be used to preparepharmaceutically acceptable addition salts.

A “solvate” is formed by the interaction of a solvent and a compound.Suitable solvents include, for example, water and alcohols (e.g.,ethanol). Solvates include hydrates having any ratio of compound towater, such as monohydrates, dihydrates and hemi-hydrates.

A “chelate” is formed by the coordination of a compound to a metal ionat two (or more) points. The term “compound” is intended to includechelates of compounds. Similarly, “salts” includes chelates of salts and“solvates” includes chelates of solvates.

A “non-covalent complex” is formed by the interaction of a compound andanother molecule wherein a covalent bond is not formed between thecompound and the molecule. For example, complexation can occur throughvan der Waals interactions, hydrogen bonding, and electrostaticinteractions (also called ionic bonding). Such non-covalent complexesare included in the term “compound”.

The term “prodrug” refers to a substance administered in an inactive orless active form that is then transformed (e.g., by metabolic processingof the prodrug in the body) into an active compound. The rationalebehind administering a prodrug is to optimize absorption, distribution,metabolism, and/or excretion of the drug. Prodrugs may be obtained bymaking a derivative of an active compound (e.g., a compound of Formula Ior another compound disclosed and/or described herein) that will undergoa transformation under the conditions of use (e.g., within the body) toform the active compound. The transformation of the prodrug to theactive compound may proceed spontaneously (e.g., by way of a hydrolysisreaction) or it can be catalyzed or induced by another agent (e.g., anenzyme, light, acid or base, and/or temperature). The agent may beendogenous to the conditions of use (e.g., an enzyme present in thecells to which the prodrug is administered, or the acidic conditions ofthe stomach) or the agent may be supplied exogenously. Prodrugs can beobtained by converting one or more functional groups in the activecompound into another functional group, which is then converted back tothe original functional group when administered to the body. Forexample, a hydroxyl functional group can be converted to a sulfonate,phosphate, ester or carbonate group, which in turn can be hydrolyzed invivo back to the hydroxyl group. Similarly, an amino functional groupcan be converted, for example, into an amide, carbamate, imine, urea,phosphenyl, phosphoryl or sulfenyl functional group, which can behydrolyzed in vivo back to the amino group. A carboxyl functional groupcan be converted, for example, into an ester (including silyl esters andthioesters), amide or hydrazide functional group, which can behydrolyzed in vivo back to the carboxyl group. Examples of prodrugsinclude, but are not limited to, phosphate, acetate, formate andbenzoate derivatives of functional groups (such as alcohol or aminegroups) present in the compounds of Formula I and other compoundsdisclosed and/or described herein.

The compounds disclosed and/or described herein can be enriched isotopicforms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. Inone embodiment, the compound contains at least one deuterium atom. Suchdeuterated forms can be made, for example, by the procedure described inU.S. Pat. Nos. 5,846,514 and 6,334,997. Such deuterated compounds mayimprove the efficacy and increase the duration of action of compoundsdisclosed and/or described herein. Deuterium substituted compounds canbe synthesized using various methods, such as those described in: Dean,D., Recent Advances in the Synthesis and Applications of RadiolabeledCompounds for Drug Discovery and Development, Curr. Pharm. Des., 2000;6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds viaOrganometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; andEvans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem.,1981, 64(1-2), 9-32.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in pharmaceutical compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the pharmaceutical compositions.

The term “active agent” is used to indicate a compound that hasbiological activity. In some embodiments, an “active agent” is acompound having therapeutic utility. In some embodiments, the compoundenhances at least one aspect of skeletal muscle function or activity,such as power output, skeletal muscle force, skeletal muscle endurance,oxygen consumption, efficiency, and/or calcium sensitivity. In someembodiments, an active agent is a compound of Formula I, or apharmaceutically acceptable salt thereof.

The terms “patient” and “subject” refer to an animal, such as a mammalbird or fish. In some embodiments, the patient or subject is a mammal.Mammals include, for example, mice, rats, dogs, cats, pigs, sheep,horses, cows and humans. In some embodiments, the patient or subject isa human, for example a human that has been or will be the object oftreatment, observation or experiment. The compounds, compositions andmethods described herein can be useful in both human therapy andveterinary applications.

As used herein, “skeletal muscle” includes skeletal muscle tissue aswell as components thereof, such as skeletal muscle fibers, themyofibrils comprising the skeletal muscle fibers, the skeletal sarcomerewhich comprises the myofibrils, and the various components of theskeletal sarcomere described herein, including skeletal myosin, actin,tropomyosin, troponin C, troponin I, troponin T and fragments andisoforms thereof. In some embodiments, “skeletal muscle” includes fastskeletal muscle tissue as well as components thereof, such as fastskeletal muscle fibers, the myofibrils comprising the fast skeletalmuscle fibers, the fast skeletal sarcomere which comprises themyofibrils, and the various components of the fast skeletal sarcomeredescribed herein, including fast skeletal myosin, actin, tropomyosin,troponin C, troponin I, troponin T and fragments and isoforms thereof.Skeletal muscle does not include cardiac muscle or a combination ofsarcomeric components that occurs in such combination in its entirety incardiac muscle.

As used herein, the term “therapeutic” refers to the ability to modulatethe contractility of fast skeletal muscle. As used herein, “modulation”(and related terms, such as “modulate”, “modulated”, “modulating”)refers to a change in function or efficiency of one or more componentsof the fast skeletal muscle sarcomere, including myosin, actin,tropomyosin, troponin C, troponin I, and troponin T from fast skeletalmuscle, including fragments and isoforms thereof, as a direct orindirect response to the presence of a compound described herein,relative to the activity of the fast skeletal sarcomere in the absenceof the compound. The change may be an increase in activity(potentiation) or a decrease in activity (inhibition), and may be due tothe direct interaction of the compound with the sarcomere, or due to theinteraction of the compound with one or more other factors that in turnaffect the sarcomere or one or more of its components. In someembodiments, modulation is a potentiation of function or efficiency ofone or more components of the fast skeletal muscle sarcomere, includingmyosin, actin, tropomyosin, troponin C, troponin I, and troponin T fromfast skeletal muscle, including fragments and isoforms thereof.Modulation may be mediated by any mechanism and at any physiologicallevel, for example, through sensitization of the fast skeletal sarcomereto contraction at lower Ca²⁺ concentrations. As used herein,“efficiency” or “muscle efficiency” means the ratio of mechanical workoutput to the total metabolic cost.

The term “therapeutically effective amount” or “effective amount” refersto that amount of a compound disclosed and/or described herein that issufficient to affect treatment, as defined herein, when administered toa patient in need of such treatment. A therapeutically effective amountof a compound may be an amount sufficient to treat a disease responsiveto modulation of fast skeletal muscle. The therapeutically effectiveamount will vary depending upon, for example, the subject and diseasecondition being treated, the weight and age of the subject, the severityof the disease condition, the particular compound, the dosing regimen tobe followed, timing of administration, the manner of administration, allof which can readily be determined by one of ordinary skill in the art.The therapeutically effective amount may be ascertained experimentally,for example by assaying blood concentration of the chemical entity, ortheoretically, by calculating bioavailability.

“Treatment” (and related terms, such as “treat”, “treated”, “treating”)includes one or more of: preventing a disease or disorder (i.e., causingthe clinical symptoms of the disease or disorder not to develop);inhibiting a disease or disorder; slowing or arresting the developmentof clinical symptoms of a disease or disorder; and/or relieving adisease or disorder (i.e., causing relief from or regression of clinicalsymptoms). The term encompasses situations where the disease or disorderis already being experienced by a patient, as well as situations wherethe disease or disorder is not currently being experienced but isexpected to arise. The term covers both complete and partial reductionor prevention of the condition or disorder, and complete or partialreduction of clinical symptoms of a disease or disorder. Thus, compoundsdescribed and/or disclosed herein may prevent an existing disease ordisorder from worsening, assist in the management of the disease ordisorder, or reduce or eliminate the disease or disorder. When used in aprophylactic manner, the compounds disclosed and/or described herein mayprevent a disease or disorder from developing or lessen the extent of adisease or disorder that may develop.

As used herein, “power output” of a muscle means work/cycle time and maybe scaled up from PoLo/cycle time units based on the properties of themuscle. Power output may be modulated by changing, for example,activating parameters during cyclical length changes, including timingof activation (phase of activation) and the period of activation (dutycycle.)

“ATPase” refers to an enzyme that hydrolyzes ATP. ATPases includeproteins comprising molecular motors such as the myosins.

As used herein, “selective binding” or “selectively binding” refers topreferential binding to a target protein in one type of muscle or musclefiber as opposed to other types. For example, a compound selectivelybinds to fast skeletal troponin C if the compound preferentially bindstroponin C in the troponin complex of a fast skeletal muscle fiber orsarcomere in comparison with troponin C in the troponin complex of aslow muscle fiber or sarcomere or with troponin C in the troponincomplex of a cardiac sarcomere.

Provided is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Z¹, Z², Z³ and Z⁴ are each independently selected from N and CR¹,provided that at least one of Z¹, Z², Z³ and Z⁴ is N and at least one ofZ¹, Z², Z³ and Z⁴ is CR¹;

R¹, at each occurrence, is independently selected from hydrogen,halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)OR^(a), C(O)NR^(b)R^(c),OR^(a), NR^(b)R^(c), C₆₋₁₀ aryl and 5-10 membered heteroaryl;

R² is selected from C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, 5-10membered heteroaryl and NR^(b)R^(c), wherein each of the C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl and 5-10 membered heteroarylgroups is optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 membered heterocycloalkyl,(CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 membered heteroaryl groups isoptionally substituted with 1, 2, 3, 4 or 5 R^(f) substituents;

R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c) and SO₂R^(a);

R⁵ and R⁶ are each independently selected from hydrogen, halogen, C₁₋₆alkyl and C₁₋₆ haloalkyl;

or alternatively, R⁵ and R⁶ together with the carbon atom to which theyare bound form a group selected from C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,3-8 membered heterocycloalkyl and 3-8 membered heterocycloalkenyl, eachoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c),C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a),SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R⁷ is selected from C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl and 5-10membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents;

R⁸ and R⁹, at each occurrence, are each independently selected fromhydrogen, halogen and C₁₋₆ alkyl;

X is selected from a bond, —(CH₂)_(p)—, —(CH₂)_(p)C(O)(CH₂)_(q)—,—(CH₂)_(p)O(CH₂)_(q)—, —(CH₂)_(p)S(CH₂)_(q)—,—(CH₂)_(p)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)C(O)O(CH₂)_(q)—,—(CH₂)_(p)OC(O)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)(CH₂)_(q)—,—(CH₂)_(p)C(O)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)NR^(d)(CH₂)_(q)—,—(CH₂)_(p)NR^(d)SO₂(CH₂)_(q)—, and —(CH₂)_(p)SO₂NR^(d)(CH₂)_(q)—;

R^(a), at each occurrence, is independently selected from hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents;

R^(b) and R^(c), at each occurrence, are each independently selectedfrom hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl, 5-10 memberedheteroaryl, C(O)R^(g), C(O)OR^(g), C(O)NR^(i)R^(j) and SO₂R^(g), whereineach of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents;

R^(d), at each occurrence, is independently selected from hydrogen andC₁₋₆ alkyl;

R^(e), at each occurrence, is independently selected from hydrogen, CN,OH, C₁₋₆ alkoxy, C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R^(f), at each occurrence, is independently selected from halogen, CN,OR^(h), OC(O)R^(h), OC(O)OR^(h), OC(O)NR^(i)R^(j), NR^(i)R^(j),NR^(d)C(O)R^(h), NR^(d)C(O)OR^(h), NR^(d)C(O)NR^(i)R^(j),NR^(d)C(O)C(O)NR^(i)R^(j), NR^(d)C(S)R^(h), NR^(d)C(S)OR^(h),NR^(d)C(S)NR^(i)R^(j), NR^(d)C(NR^(e))NR^(i)R^(j), NR^(d)S(O)R^(h),NR^(d)SO₂R^(h), NR^(d)SO₂NR^(i)R^(j), C(O)R^(h), C(O)OR^(h),C(O)NR^(i)R^(j), C(S)R^(h), C(S)OR^(h), C(S)NR^(i)R^(j),C(NR^(e))NR^(i)R^(j), SR^(h), S(O)R^(h), SO₂R^(h), SO₂NR^(i)R^(j), C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(k)substituents;

or two R^(f) substituents bound to a single carbon atom, together withthe carbon atom to which they are both bound, form a group selected fromcarbonyl, C₃₋₈ cycloalkyl and 3-8 membered heterocycloalkyl;

R^(g), at each occurrence, is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, phenyl, naphthyl, and C₇₋₁₁ aralkyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN,OH, C₁₋₆ alkoxy, C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R^(h), at each occurrence, is independently selected from hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(k)substituents;

R^(i) and R^(j), at each occurrence, are each independently selectedfrom hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl, 5-10 memberedheteroaryl, C(O)R^(g), and C(O)OR^(g), wherein each of the C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl andC₁₋₆ haloalkyl;

R^(k), at each occurrence, is independently selected from halogen, CN,oxo, OH, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, NHC(O)C₁₋₆alkyl, NHC(O)C₇₋₁₁ aralkyl, NHC(O)OC₁₋₆ alkyl, NHC(O)OC₇₋₁₁ aralkyl,C(O)C₁₋₆ alkyl, C(O)C₇₋₁₁ aralkyl, C(O)OC₁₋₆ alkyl, C(O)OC₇₋₁₁ aralkyl,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein eachC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₇₋₁₁ aralkyl substituent isoptionally substituted with 1, 2 or 3 substituents selected from OH,C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, NHC(O)C₁₋₆ alkyl,NHC(O)C₇₋₁₁ aralkyl, NHC(O)OC₁₋₆ alkyl, and NHC(O)OC₇₋₁₁ aralkyl;

-   -   m is 0, 1 or 2;    -   n, at each occurrence, independently is 0, 1 or 2;    -   p is 0, 1 or 2; and    -   q is 0, 1 or 2.

In some embodiments of compounds of Formula I, Z¹ and Z² are each N, oneof Z³ and Z⁴ is N, and the other of Z³ and Z⁴ is CR¹.

In some embodiments of compounds of Formula I, Z¹, Z² and Z³ are each Nand Z⁴ is CR¹, i.e., a compound of Formula II, or a pharmaceuticallyacceptable salt thereof:

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, X and m are as defined herein.

In some embodiments of compounds of Formula I, Z¹, Z² and Z⁴ are each Nand Z³ is CR¹, i.e., a compound of Formula III, or a pharmaceuticallyacceptable salt thereof:

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, X and m are as defined herein.

In some embodiments of compounds of Formula I, one of Z¹ and Z² is N,the other of Z¹ and Z² is CR¹, and Z³ and Z⁴ are each CR¹.

In some embodiments of compounds of Formula I, Z¹, Z³ and Z⁴ are eachCR¹ and Z² is N, i.e., a compound of Formula IV, or a pharmaceuticallyacceptable salt thereof:

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, X and m are as defined herein.

In some embodiments of compounds of Formula I, Z², Z³ and Z⁴ are eachCR¹ and Z¹ is N, i.e., a compound of Formula V, or a pharmaceuticallyacceptable salt thereof:

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, X and m are as defined herein.

In some embodiments of compounds of Formula I, II, III, IV or V, m is 0,i.e., a compound of Formula II(a), III(a), IV(a) or V(a), or apharmaceutically acceptable salt thereof:

wherein R¹, R², R⁴, R⁵, R⁶, R⁷ and X are as defined herein.

In some embodiments of compounds of Formula I, II, III, IV or V, m is 1,i.e., a compound of Formula II(b), III(b), IV(b) or V(b), or apharmaceutically acceptable salt thereof:

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), one of R⁵ and R⁶ ishydrogen and the other is C₁₋₆ alkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶ are eachindependently C₁₋₆ alkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶ are eachmethyl.

In some embodiments, the compounds are of Formula II(c) or II(d), or apharmaceutically acceptable salt thereof:

wherein R¹, R², R⁴, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments, the compounds are of Formula III(c) or III(d), or apharmaceutically acceptable salt thereof:

wherein R¹, R², R⁴, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments, the compounds are of Formula IV(c) or IV(d), or apharmaceutically acceptable salt thereof:

wherein R¹, R², R⁴, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments, the compounds are of Formula V(c) or V(d), or apharmaceutically acceptable salt thereof:

wherein R¹, R², R⁴, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶ togetherwith the carbon atom to which they are bound form C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 memberedheterocycloalkenyl, each optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶, togetherwith the carbon to which they are bound, form C₃₋₆ cycloalkyl optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN,oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶, togetherwith the carbon to which they are bound, form cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, each optionally substituted with 1, 2, 3, 4or 5 substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶, togetherwith the carbon to which they are bound, form cyclobutyl optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN,oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶, togetherwith the carbon to which they are bound, form cyclobutyl substitutedwith 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo,OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a),C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl andC₁₋₆ haloalkyl, wherein the substituent and R⁷ are in a transconfiguration with respect to one another on the cyclobutyl ring.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶, togetherwith the carbon to which they are bound, form cyclobutyl substitutedwith one substituent selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl,wherein the substituent and R⁷ are in a cis configuration with respectto one another on the cyclobutyl ring.

In some embodiments, the compounds are of Formula II(e) or II(f), or apharmaceutically acceptable salt thereof:

wherein R^(m) and R^(n) are each independently selected from hydrogenand halogen, and R¹, R², R⁴, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments, the compounds are of Formula III(e) or III(f), or apharmaceutically acceptable salt thereof:

wherein R^(m) and R^(n) are each independently selected from hydrogenand halogen, and R¹, R², R⁴, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments, the compounds are of Formula IV(e) or IV(f), or apharmaceutically acceptable salt thereof:

wherein R^(m) and R^(n) are each independently selected from hydrogenand halogen, and R¹, R², R⁴, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments, the compounds are of Formula V(e) or V(f), or apharmaceutically acceptable salt thereof:

wherein R^(m) and R^(n) are each independently selected from hydrogenand halogen, and R¹, R², R⁴, R⁷, R⁸, R⁹ and X are as defined herein.

In some embodiments of compounds of Formula II(e), IV), III(e), III(f),IV(e), IV(f), V(e) or V(f), R^(m) and R^(n) are each hydrogen.

In some embodiments compounds of Formula II(e), IV), III(e), III(f),IV(e), IV(f), V(e) or V(f), R^(m) and R^(n) are each halogen.

In some embodiments compounds of Formula II(e), IV), III(e), III(f),IV(e), IV(f), V(e) or V(f), R^(m) and R^(n) are each fluorine.

In some embodiments compounds of Formula II(e), IV), III(e), III(f),IV(e), IV(f), V(e) or V(f), one of R^(m) and R^(n) is hydrogen and theother is halogen. In some embodiments of such compounds, the halogen andR⁷ are in a trans configuration with respect to one another on thecyclobutyl ring. In some embodiments of such compounds, the halogen andR⁷ are in a cis configuration with respect to one another on thecyclobutyl ring.

In some embodiments compounds of Formula II(e), IV), III(e), III(f),IV(e), IV(f), V(e) or V(f), one of R^(m) and R^(n) is hydrogen and theother is fluorine. In some embodiments of such compounds, the fluorineand R⁷ are in a trans configuration with respect to one another on thecyclobutyl ring. In some embodiments of such compounds, the fluorine andR⁷ are in a cis configuration with respect to one another on thecyclobutyl ring.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶, togetherwith the carbon atom to which they are bound, form 3-6 memberedheterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶, togetherwith the carbon atom to which they are bound, form aziridine, azetidine,pyrrolidine, oxirane, oxetane or tetrahydrofuran, each of which isoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c),C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a),SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶ are eachindependently C₁₋₆ alkyl, or R⁵ and R⁶ together with the carbon atom towhich they are bound form C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl or 3-8 membered heterocycloalkenyl, eachoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c),C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a),SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶ are eachmethyl, or R⁵ and R⁶ together with the carbon atom to which they arebound form C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl or 3-8 membered heterocycloalkenyl, each optionallysubstituted with 1, 2, 3, 4 or 5 substituents selected from halogen, CN,oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶ are eachindependently C₁₋₆ alkyl, or R⁵ and R⁶, together with the carbon towhich they are bound, form a group selected from cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR^(a),OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a),C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl andC₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), III,III(a), III(b), IV, IV(a), IV(b) V, V(a) or V(b), R⁵ and R⁶ are eachmethyl, or R⁵ and R⁶, together with the carbon to which they are bound,form cyclobutyl optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a),NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R⁷ is selected from C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryland 5-10 membered heteroaryl, each optionally substituted with 1, 2, 3,4 or 5 substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R⁷ is phenyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R⁷ is selected from phenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2-methylphenyl, 3-methylphenyl, 2, 4-dimethylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 2-(hydroxymethyl)phenyl, 3-(hydroxymethyl)phenyl,4-(hydroxymethyl)phenyl, 2-(aminomethyl)phenyl, 3-(aminomethyl)phenyl,4-(aminomethyl)phenyl, 2-phenol, 3-phenol, 4-phenol, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-difluoromethoxyphenyl,3-difluoromethoxyphenyl, 4-difluoromethoxyphenyl,2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-benzamine, 3-benzamide, 4-benzamide, N-methyl-2-benzamine,N-methyl-3-benzamide, N-methyl-4-benzamide, N,N-dimethyl-2-benzamine,N,N-dimethyl-3-benzamide, and N,N-dimethyl-4-benzamide.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R⁷ is 5-10 membered heteroaryl optionally substituted with 1,2, 3, 4 or 5 substituents selected from halogen, CN, oxo, OR^(a),OC(O)R^(a), OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R⁷ is pyridyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R⁷ is selected from 2-pyridyl, 3-pyridyl and 4-pyridyl, eachoptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromhalogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), OC(O)NR^(b)R^(c),NR^(b)R^(c), NR^(d)C(O)R^(a), NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c),NR^(d)C(O)C(O)NR^(b)R^(c), NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a),NR^(d)C(S)NR^(b)R^(c), NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a),NR^(d)SO₂R^(a), NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a),C(O)NR^(b)R^(c), C(S)R^(a), C(S)OR^(a), C(S)NR^(b)R^(c),C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl, and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a) or V(b), R⁷ is selected from pyrid-2-yl, 3-fluoro-pyrid-2-yl,4-fluoro-pyrid-2-yl, 5-fluoro-pyrid-2-yl, 6-fluoro-pyrid-2-yl,3-chloro-pyrid-2-yl, 4-chloro-pyrid-2-yl, 5-chloro-pyrid-2-yl,6-chloro-pyrid-2-yl, 3-cyano-pyrid-2-yl, 4-cyano-pyrid-2-yl,5-cyano-pyrid-2-yl, 6-cyano-pyrid-2-yl, 3-methyl-pyrid-2-yl,4-methyl-pyrid-2-yl, 5-methyl-pyrid-2-yl, 6-methyl-pyrid-2-yl,3-difluoromethyl-pyrid-2-yl, 4-difluoromethyl-pyrid-2-yl,5-difluoromethyl-pyrid-2-yl, 6-difluoromethyl-pyrid-2-yl,3-trifluoromethyl-pyrid-2-yl, 4-trifluoromethyl-pyrid-2-yl,5-trifluoromethyl-pyrid-2-yl, 6-trifluoromethyl-pyrid-2-yl,3-hydroxymethyl-pyrid-2-yl, 4-hydroxymethyl-pyrid-2-yl,5-hydroxymethyl-pyrid-2-yl, 6-hydroxymethyl-pyrid-2-yl,3-aminomethyl-pyrid-2-yl, 4-aminomethyl-pyrid-2-yl,5-aminomethyl-pyrid-2-yl, 6-aminomethyl-pyrid-2-yl,3-hydroxy-pyrid-2-yl, 4-hydroxy-pyrid-2-yl, 5-hydroxy-pyrid-2-yl,6-hydroxy-pyrid-2-yl, 3-methoxy-pyrid-2-yl, 4-methoxy-pyrid-2-yl,5-methoxy-pyrid-2-yl, 6-methoxy-pyrid-2-yl,3-difluoromethoxy-pyrid-2-yl, 4-difluoromethoxy-pyrid-2-yl,5-difluoromethoxy-pyrid-2-yl, 6-difluoromethoxy-pyrid-2-yl,3-trifluoromethoxy-pyrid-2-yl, 4-trifluoromethoxy-pyrid-2-yl,5-trifluoromethoxy-pyrid-2-yl, 6-trifluoromethoxy-pyrid-2-yl,3-methylthio-pyrid-2-yl, 4-methylthio-pyrid-2-yl,5-methylthio-pyrid-2-yl, 6-methylthio-pyrid-2-yl,3-carboxamide-pyrid-2-yl, 4-carboxamide-pyrid-2-yl,5-carboxamide-pyrid-2-yl, 6-carboxamide-pyrid-2-yl and3-fluoro-6-methyl-pyrid-2-yl.

In some embodiments of compounds of Formula I, II, III, IV(a), IV(b),V(a) or V(b), R⁷ is selected from pyrid-3-yl, 2-fluoro-pyrid-3-yl,4-fluoro-pyrid-3-yl, 5-fluoro-pyrid-3-yl, 6-fluoro-pyrid-3-yl,2-chloro-pyrid-3-yl, 4-chloro-pyrid-3-yl, 5-chloro-pyrid-3-yl,6-chloro-pyrid-3-yl, 2-cyano-pyrid-3-yl, 4-cyano-pyrid-3-yl,5-cyano-pyrid-3-yl, 6-cyano-pyrid-3-yl, 2-methyl-pyrid-3-yl,4-methyl-pyrid-3-yl, 5-methyl-pyrid-3-yl, 6-methyl-pyrid-3-yl,2-difluoromethyl-pyrid-3-yl, 4-difluoromethyl-pyrid-3-yl,5-difluoromethyl-pyrid-3-yl, 6-difluoromethyl-pyrid-3-yl,2-trifluoromethyl-pyrid-3-yl, 4-trifluoromethyl-pyrid-3-yl,5-trifluoromethyl-pyrid-3-yl, 6-trifluoromethyl-pyrid-3-yl,2-hydroxymethyl-pyrid-3-yl, 4-hydroxymethyl-pyrid-3-yl,5-hydroxymethyl-pyrid-3-yl, 6-hydroxymethyl-pyrid-3-yl,2-aminomethyl-pyrid-3-yl, 4-aminomethyl-pyrid-3-yl,5-aminomethyl-pyrid-3-yl, 6-aminomethyl-pyrid-3-yl,2-hydroxy-pyrid-3-yl, 4-hydroxy-pyrid-3-yl, 5-hydroxy-pyrid-3-yl,6-hydroxy-pyrid-3-yl, 2-methoxy-pyrid-3-yl, 4-methoxy-pyrid-3-yl,5-methoxy-pyrid-3-yl, 6-methoxy-pyrid-3-yl,2-difluoromethoxy-pyrid-3-yl, 4-difluoromethoxy-pyrid-3-yl,5-difluoromethoxy-pyrid-3-yl, 6-difluoromethoxy-pyrid-3-yl,2-trifluoromethoxy-pyrid-3-yl, 4-trifluoromethoxy-pyrid-3-yl,5-trifluoromethoxy-pyrid-3-yl, 6-trifluoromethoxy-pyrid-3-yl,2-methylthio-pyrid-3-yl, 4-methylthio-pyrid-3-yl,5-methylthio-pyrid-3-yl, 6-methylthio-pyrid-3-yl,2-carboxamide-pyrid-3-yl, 4-carboxamide-pyrid-3-yl,5-carboxamide-pyrid-3-yl and 6-carboxamide-pyrid-3-yl.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is selected from a bond, —(CH₂)_(p)—,—(CH₂)_(p)C(O)(CH₂)_(q)—, —(CH₂)_(p)O(CH₂)_(q)—, —(CH₂)_(p)S(CH₂)_(q)—,—(CH₂)_(p)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)C(O)O(CH₂)_(q)—,—(CH₂)_(p)OC(O)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)(CH₂)_(q)—,—(CH₂)_(p)C(O)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)NR^(d)(CH₂)_(q)—,—(CH₂)_(p)NR^(d)SO₂(CH₂)_(q)—, and —(CH₂)_(p)SO₂NR^(d)(CH₂)_(q)—.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is a bond.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is —O—.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is selected from —CH₂O— and —OCH₂—.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is —NR^(d)—.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is selected from —CH₂NR^(d)— and —NR^(d)CH₂—.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is selected from NR^(d)C(O)— and —C(O)NR^(d)—.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is selected from CH₂NR^(d)C(O)— and —C(O)NR^(d)CH₂—.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and NR^(b)R^(c), wherein each of the C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl and 5-10 membered heteroarylgroups is optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 membered heterocycloalkyl,(CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 membered heteroaryl groups isoptionally substituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is phenyl optionally substituted with 1, 2, 3, 4 or 5substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is phenyl substituted with 1, 2, 3, 4 or 5 substituentsselected from halogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 membered heterocycloalkyl,(CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 membered heteroaryl groups isoptionally substituted with 1, 2, 3, 4 or 5 R^(f) substituents; whereinat least one substitutent is bonded at the meta position.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is phenyl substituted with a substituent selected from(CH₂)_(n)C(O)OR^(a) and (CH₂)_(n)C(O)NR^(b)R^(c); and optionallysubstituted with 1, 2 or 3 additional substituents selected fromhalogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n) NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 membered heterocycloalkyl,(CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 membered heteroaryl groups isoptionally substituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is phenyl substituted with a substituent selected fromC(O)OH, C(O)NH₂, C(O)OC₁₋₆ alkyl, C(O)NHC₁₋₆ alkyl and C(O)N(C₁₋₆alkyl)₂; and optionally substituted with 1, 2 or 3 additionalsubstituents selected from halogen, C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is phenyl substituted at the meta position with asubstituent selected from (CH₂)_(n)C(O)OR^(a) and(CH₂)_(n)C(O)NR^(b)R^(c); and optionally substituted with 1, 2 or 3additional substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is phenyl substituted at the meta position with asubstituent selected from (CH₂)_(n)C(O)OR^(a) and(CH₂)_(n)C(O)NR^(b)R^(c), and optionally substituted with 1, 2 or 3additional substituents selected from halogen, hydroxyl, CN, C₁₋₆ alkyland C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is phenyl substituted at the meta position with asubstituent selected from C(O)OH, C(O)NH₂, C(O)OC₁₋₆ alkyl, C(O)NHC₁₋₆alkyl and C(O)N(C₁₋₆ alkyl)₂; and optionally substituted with 1, 2 or 3additional substituents selected from halogen, hydroxyl, CN, C₁₋₆ alkyland C₁₋₆ haloalkyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is phenyl substituted with (CH₂)_(n)NR^(d)C(O)R^(a), whereinR^(a) is C₁₋₆ alkyl or 3-8 membered heterocycloalkyl, each optionallysubstituted with 1, 2 or 3 additional substituents selected fromhalogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl; and optionally substituted with 1, 2 or 3additional substituents selected from halogen, CN, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is phenyl substituted with (CH₂)_(n)NR^(d)C(O)R^(a), whereinR^(a) is selected from C₁₋₆ alkyl, C₁₋₆ alkyl-OH and C₁₋₆ alkyl-NH₂,each optionally substituted with 1, 2 or 3 additional substituentsselected from halogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, and (CH₂)_(n)5-10 memberedheteroaryl; and optionally substituted with 1, 2 or 3 additionalsubstituents selected from halogen, CN, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from 3-benzamide, N-methyl-3-benzamide,N,N-dimethyl-3-benzamide, 4-fluoro-3-benzamide,N-methyl-4-fluoro-3-benzamide, N,N-dimethyl-4-fluoro-3-benzamide,3-benzoic acid, methyl-3-benzoate, 4-fluoro-3-benzoic acid, andmethyl-4-fluoro-3-benzoate.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is 5-10 membered heteroaryl optionally substituted with 1,2, 3, 4 or 5 substituents selected from halogen, CN, oxo,(CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 membered heterocycloalkyl,(CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 membered heteroaryl groups isoptionally substituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl,triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl,thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyland tetrazolyl, each optionally substituted with 1, 2, 3 or 4substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl,triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl,thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyland tetrazolyl, each optionally substituted with a substituent selectedfrom (CH₂)_(n)C(O)OR^(a) and (CH₂)_(n)C(O)NR^(b)R^(c); and optionallysubstituted with 1, 2 or 3 additional substituents selected fromhalogen, CN, oxo, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e)) NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 membered heterocycloalkyl,(CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 membered heteroaryl groups isoptionally substituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl andtriazyl, each optionally substituted with (CH₂)_(n)C(O)NR^(b)R^(c).

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl,isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,imidazolyl, triazolyl and tetrazolyl, each optionally substituted with(CH₂)_(n)C(O)NR^(b)R^(c).

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl andtriazyl, each optionally substituted with (CH₂)_(n)C(O)NH₂.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl,isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,imidazolyl, triazolyl and tetrazolyl, each optionally substituted with(CH₂)_(n)C(O)NH₂.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl,triazyl, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl,thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyland tetrazolyl, each optionally substituted with(CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a) is C₁₋₆ alkyl or 3-8 memberedheterocycloalkyl, each optionally substituted with 1, 2 or 3substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from pyridyl, pyrimidyl, pyrazyl, pyridazyl andtriazyl, each optionally substituted with (CH₂)_(n)NR^(d)C(O)R^(a),wherein R^(a) is selected from C₁₋₆ alkyl, C₁₋₆ alkyl-OH and C₁₋₆alkyl-NH₂, each optionally substituted with 1, 2 or 3 substituentsselected from halogen, CN, (CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a),(CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from furanyl, pyrrolyl, thiophenyl, thiazolyl,isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,imidazolyl, triazolyl and tetrazolyl, each optionally substituted with(CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a) is selected from C₁₋₆ alkyl,C₁₋₆ alkyl-OH and C₁₋₆ alkyl-NH₂, each optionally substituted with 1, 2or 3 substituents selected from halogen, CN, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from indolyl, indazolyl, benzimidazolyl,benzoxazolyl and benzoisoxazolyl, each optionally substituted with 1, 2,3 or 4 substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from 1H-indazol-6-yl, 1H-indazol-5-yl,1H-indazol-4-yl, 3-amino(1H-indazol-5-yl), 3-amino(1H-indazol-6-yl),3-amino(1H-indazol-7-yl), 1-methyl(1H-indazol-6-yl),3-methyl(1H-indazol-6-yl), 3-amino-1-methyl(1H-indazol-5-yl),3-cyano(1H-indazol-5-yl), 3-carboxamide(1H-indazol-5-yl),3-carboxamidine(1H-indazol-5-yl), 3-vinyl(1H-indazol-5-yl),3-ethyl(1H-indazol-5-yl), 3-acetamide(1H-indazol-5-yl),3-methylsulfonylamine(1H-indazol-5-yl),3-methoxycarboxamide(1H-indazol-5-yl), 3-methylamino(1H-indazol-5-yl),3-dimethylamino(1H-indazol-5-yl), 3-ethylamino(1H-indazol-5-yl),3-(2-aminoethyl)amino(1H-indazol-5-yl),3-(2-hydroxyethyl)amino(1H-indazol-5-yl),3-[(methylethyl)amino](1H-indazol-5-yl), 6-benzimidazol-5-yl,6-(2-methylbenzimidazol-5-yl), 2-aminobenzimidazol-5-yl,2-hydroxybenzimidazol-5-yl, 2-acetamidebenzimidazol-5-yl,3-aminobenzo[3,4-d]isoxazol-5-yl, 3-aminobenzo[d]isoxazol-6-yl,3-aminobenzo[d]isoxazol-7-yl, 2-methylbenzoxazol-5-yl and2-methylbenzoxazol-6-yl.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from 3-6 membered heterocycloalkyl and 3-6membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4or 5 substituents selected from halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is selected from aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl, each optionally substitutedwith 1, 2, 3, 4 or 5 substituents selected from halogen, CN, oxo,(CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,(CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 membered heterocycloalkyl,(CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 membered heteroaryl groups isoptionally substituted with 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is NR^(b)R^(c), wherein R^(b) and R^(c) are as definedherein.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R² is NR^(b)R^(c), wherein one of R^(b) and R^(c) is hydrogenand the other is C₁₋₆ alkyl optionally substituted with 1, 2, 3, 4 or 5R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is —C(O)— and R² is NR^(b)R^(c), wherein R^(b) and R^(c) areas defined herein.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is —C(O)— and R² is NR^(b)R^(c), wherein one of R^(b) andR^(c) is hydrogen and the other is C₁₋₆ alkyl optionally substitutedwith 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is —(CH₂)_(p)— and R² is NR^(b)R^(c), wherein R^(b) and R^(c)are as defined herein.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), X is —(CH₂)_(p)— and R² is NR^(b)R^(c), wherein one of R^(b)and R^(c) is hydrogen and the other is C₁₋₆ alkyl optionally substitutedwith 1, 2, 3, 4 or 5 R^(f) substituents.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R¹, at each occurrence, is independently selected fromhydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)OR^(a),C(O)NR^(b)R^(c), OR^(a), NR^(b)R^(c), C₆₋₁₀ aryl and 5-10 memberedheteroaryl.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R¹, at each occurrence, is independently selected fromhydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, hydroxyl, C₁₋₆alkoxy, NH₂, NHC₁₋₆ alkyl, and N(C₁₋₆ alkyl)₂.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R¹, at each occurrence, is independently selected fromhydrogen, halogen, CN, CF₃ and methyl.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R¹, at each occurrence, is hydrogen.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R⁴ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c) and SO₂R^(a).

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R⁴ is hydrogen.

In some embodiments of compounds of Formula I, II, II(a), II(b), II(c),II(d), II(e), II(f), III(a), III(b), III(c), III(d), III(e), III(f),IV(a), IV(b), IV(c), IV(d), IV(e), IV(f), V(a), V(b), V(c), V(d), V(e)or V(f), R⁴ is hydrogen and each R¹ is hydrogen.

In some embodiments of compounds of Formula I, II, II(b), II(d), II(f),III(b), III(d), III(f), IV(b), IV(d), IV(f), V(b), V(d) or V(f), R⁸ andR⁹, at each occurrence, are each independently selected from hydrogen,halogen and C₁₋₆ alkyl.

In some embodiments of compounds of Formula I, II, II(b), II(d), II(f),III(b), III(d), III(f), IV(b), IV(d), IV(f), V(b), V(d) or V(f), R⁸ andR⁹, at each occurrence, are each hydrogen.

In some embodiments, the compound is selected from the compounds inTable 2, or a pharmaceutically acceptable salt thereof.

The compounds and compositions described and/or disclosed hereinmodulate the contractility of the skeletal sarcomere. Specifically, thecompounds modulate the troponin complex of the fast skeletal musclesarcomere through one or more of fast skeletal myosin, actin,tropomyosin, troponin C, troponin I, and troponin T, and fragments andisoforms thereof. As used in this context, “modulate” means eitherincreasing or decreasing activity. In some instances, the compoundsdescribed and/or disclosed herein potentiate (i.e., increase activity)of one or more of fast skeletal myosin, actin, tropomyosin, troponin C,troponin I, and troponin T, and fragments and isoforms thereof. In otherinstances, the compounds described and/or disclosed herein inhibit(i.e., decrease activity) of one or more of fast skeletal myosin, actin,tropomyosin, troponin C, troponin I, and troponin T, and fragments andisoforms thereof.

In both preclinical and clinical settings, activators of the fastskeletal troponin complex have been shown to amplify the response offast skeletal muscle to nerve stimulation, resulting in an increase inmuscle force development at sub-maximal muscle activation (see, e.g.,Russell et al., “The Fast Skeletal Troponin Activator, CK-2017357,Increases Skeletal Muscle Force in vitro and in situ”, 2009 ExperimentalBiology Conference, New Orleans, La., April 2009). Activators of thefast skeletal troponin complex have been shown to increase thesensitivity of skinned skeletal muscle fibers to calcium, and in livingmuscle to the frequency of stimulation, each of which results in anincrease in muscle force development at sub-maximal muscle activation.Such activators have also been shown to reduce muscle fatigue and/or toincrease the overall time to fatigue in normal and low oxygenatedconditions (see, e.g., Russell et al., “The Fast Skeletal TroponinActivator, CK-2017357, Increases Skeletal Muscle Force and ReducesMuscle Fatigue in vitro and in situ”, 5th Cachexia Conference,Barcelona, Spain, December 2009; Hinken et al., “The Fast SkeletalTroponin Activator, CK-2017357, Reduces Muscle Fatigue in an in situModel of Vascular Insufficiency”, Society for Vascular Medicine's 2010Annual Meeting: 21st Annual Scientific Sessions, Cleveland, Ohio, April2010). The increase in muscle force in response to nerve input has beendemonstrated in healthy human volunteers as well (see, e.g., Hansen etal., “CK-2017357, a Novel Activator of Fast Skeletal Muscle, IncreasesIsometric Force Evoked by Electrical Stimulation of the AnteriorTibialis Muscle in Healthy Male Subjects”, Society for Neuroscience 40thAnnual Meeting: Neuroscience 2010, November 2010). Work in additionalpreclinical models of muscle function suggests that activators of thefast skeletal troponin complex also cause an increase in muscle powerand/or endurance. These pharmacological properties suggest thismechanism of action could have application in conditions, for example,where neuromuscular function is impaired.

Provided are methods for enhancing fast skeletal muscle efficiency in apatient in need thereof, comprising administering to said patient aneffective amount of a compound or composition described and/or disclosedherein that selectively binds the troponin complex of fast skeletalmuscle fiber or sarcomere. In some embodiments, the compound disclosedand/or described herein activates fast skeletal muscle fibers orsarcomeres. In some embodiments, administration of a compound disclosedand/or described herein results in an increase in fast skeletal musclepower output. In some embodiments, administration of a compounddisclosed and/or described herein results in increased sensitivity offast skeletal muscle fibers or sarcomeres to calcium ion, as compared tofast skeletal muscle fibers or sarcomeres untreated with the compound.In some embodiments, administration of a compound disclosed and/ordescribed herein results in a lower concentration of calcium ionscausing fast skeletal muscle myosin to bind to actin. In someembodiments, administration of a compound disclosed and/or describedherein results in the fast skeletal muscle fiber generating force to agreater extent at submaximal levels of muscle activation.

Also provided is a method for sensitizing a fast skeletal muscle fiberto produce force in response to a lower concentration of calcium ion,comprising contacting the fast skeletal muscle fiber with a compound orcomposition described and/or disclosed herein that selectively binds totroponin complexes in the fast skeletal muscle sarcomere. In someembodiments, contacting the fast skeletal muscle fiber with the compoundresults in activation of the fast skeletal muscle fiber at a lowercalcium ion concentration than in an untreated fast skeletal musclefiber. In some embodiments, contacting the fast skeletal muscle fiberwith the compound results in the production of increased force at alower calcium ion concentration in comparison with an untreated fastskeletal muscle fiber.

Also provided is a method for increasing time to fast skeletal musclefatigue in a patient in need thereof, comprising contacting fastskeletal muscle fibers with a compound or composition described and/ordisclosed herein that selectively binds to the troponin complexes of thefast skeletal muscle fibers. In some embodiments, the compound binds toform ligand-troponin-calcium ion complexes that activate the fastskeletal muscle fibers. In some embodiments, formation of the complexesand/or activation of the fast skeletal muscle fibers results in enhancedforce and/or increased time to fatigue as compared to untreated fastskeletal muscle fibers contacted with a similar calcium ionconcentration.

The compounds and pharmaceutical compositions described and/or disclosedherein are capable of modulating the contractility of the fast skeletalsarcomere in vivo, and can have application in both human and animaldisease. Modulation would be desirable in a number of conditions ordiseases, including, but not limited to, 1) neuromuscular disorders,such as Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy(SMA), peripheral neuropathies and myasthenia gravis; 2) disorders ofvoluntary muscle, including muscular dystrophies, myopathies andconditions of muscle wasting, such as sarcopenia and cachexia syndromes(e.g., cachexia syndromes caused by diseases such as cancer, heartfailure, chronic obstructive pulmonary disease (COPD), and chronickidney disease/dialysis), and rehabilitation-related deficits, such asthose associated with recovery from surgery (e.g. post-surgical muscleweakness) prolonged bed rest or stroke rehabilitation; 3) centralnervous system (CNS) disorders in which muscle weakness, atrophy andfatigue are prominent symptoms, such as multiple sclerosis, Parkinson'sdisease, stroke and spinal cord injury; and 4) muscle symptoms stemmingfrom systemic disorders, including Peripheral Vascular Disease (PVD) orPeripheral Arterial Disease (PAD) (e.g., claudication), metabolicsyndrome, chronic fatigue syndrome, obesity and frailty due to aging.

The compounds and compositions described and/or disclosed herein may beused to treat neuromuscular diseases, i.e., diseases that affect anypart of the nerve-muscle unit. Neuromuscular diseases include, forexample: 1) diseases of the motor unit, including but not limited toAmyotrophic Lateral Sclerosis (ALS) including bulbar and primary lateralsclerosis (PLS) variants; spinal muscular atrophy types 1-4; Kennedysyndrome; post-polio syndrome; motor neuropathies including, forexample, critical illness polyneuropathy; multifocal motor neuropathywith conduction block; Charcot-Marie-Tooth disease and other hereditarymotor and sensory neuropathies; and Guillain-Barre Syndrome, 2)disorders of the neuromuscular junction, including myasthenia gravis,Lambert-Eaton myasthenic syndrome, and prolonged neuromuscular blockadedue to drugs or toxins; and 3) peripheral neuropathies, such as acuteinflammatory demyelinating polyradiculoneuropathy, diabetic neuropathy,chronic inflammatory demyelinating polyradiculoneuropathy, traumaticperipheral nerve lesions, neuropathy of leprosy, vasculitic neuropathy,dermatomyositis/polymyositis and neuropathy of Friedreich Ataxia.

The compounds and compositions described and/or disclosed herein may beused to treat disorders of voluntary muscle. Disorders of voluntarymuscle include 1) muscular dystrophies (including, for example,Duchenne, Becker, Limb-Girdle, Facioscapulohumeral, limb girdle,Emery-Dreyfus, oculopharyngeal and congenital muscular dystrophies); and2) myopathies, such as nemaline myopathy, central core disease,congenital myopathies, mitochondrial myopathies, acute myopathy;inflammatory myopathies (such as dermatomyositis/polymyositis andinclusion body myositis), endocrine myopathies (such as those associatedwith hyper- or hypothyroidism), Cushing's or Addison's syndrome ordisease and pituitary gland disorders, metabolic myopathies (such asglycogen storage diseases, e.g., McArdle's disease, Pompe disease, etc),drug-induced myopathy (statins, ant-retroviral drugs, steroid myopathy)restrictive lung disease, sarcoidosis, Schwartz-Jampel Syndrome, focalmuscular atrophies, and distal myopathies.

The compounds and compositions described and/or disclosed herein may beused to treat or Amyotrophic Lateral Sclerosis (ALS). ALS is a diseasethat generally arises later in life (Age 50+) and has a rapidprogression from initial limb weakness to paralysis and death. Commonlife expectancy after diagnosis is 3-5 years. The cause of disease formost ALS patients is unknown (termed the spontaneous form) while a smallproportion of patients have an inherited form (familial) of disease. Thecondition causes progressive death of motor neurons through causes thatare not clear. Surviving motor units attempt to compensate for dyingones by innervating more fibers (termed sprouting) but this can onlypartially correct muscle function, as muscles are subsequently moreprone to problems of coordination and fatigue. Eventually, survivingmotor neurons die, resulting in complete paralysis of the affectedmuscle. The disease is commonly fatal through the eventual loss ofinnervation to the diaphragm, resulting in respiratory failure. Currenttreatment options for ALS are limited.

The compounds and compositions described and/or disclosed herein may beused to treat Spinal Muscular Atrophy (SMA). SMA is a genetic disorderthat arises through the mutation of a protein, SMN1, that appears to berequired for the survival and health of motor neurons. The disease ismost common in children as the majority of patients only survive until11-12 years of age. There is currently no available treatment for SMA.

The compounds and compositions described and/or disclosed herein may beused to treat myasthenia gravis. Myasthenia gravis is a chronicautoimmune neuromuscular disease wherein the body produces antibodiesthat block, alter, or destroy proteins involved in signaling at theneuromuscular junction, thus preventing muscle contraction fromoccurring. These proteins include nicotinic acetylcholine receptor(AChR) or, less frequently, a muscle-specific tyrosine kinase (MuSK)involved in AChR clustering (see, e.g., Drachman, N. Eng. J. of Med.,330:1797-1810, 1994). The disease is characterized by varying degrees ofweakness of the skeletal (voluntary) muscles of the body. The hallmarkof myasthenia gravis is muscle weakness that increases during periods ofactivity and improves after periods of rest. Although myasthenia gravismay affect any voluntary muscle, certain muscles, such as those thatcontrol eye and eyelid movement, facial expression, chewing, talking,and swallowing are often, but not always, involved in the disorder. Themuscles that control breathing and neck and limb movements may also beaffected. In most cases, the first noticeable symptom is weakness of theeye muscles. In others, difficulty in swallowing and slurred speech maybe the first signs. The degree of muscle weakness involved in myastheniagravis varies greatly among patients, ranging from a localized form,limited to eye muscles (ocular myasthenia), to a severe or generalizedform in which many muscles—sometimes including those that controlbreathing—are affected. Symptoms, which vary in type and severity, mayinclude a drooping of one or both eyelids (ptosis), blurred or doublevision (diplopia) due to weakness of the muscles that control eyemovements, unstable or waddling gait, weakness in arms, hands, fingers,legs, and neck, a change in facial expression, difficulty in swallowingand shortness of breath, and impaired speech (dysarthria). Generalizedweakness develops in approximately 85% of patients.

The compounds and compositions described and/or disclosed herein may beused to treat sarcopenia, e.g., sarcopenia associated with aging ordisease (e.g. HIV infection). Sarcopenia is characterized by a loss ofskeletal muscle mass, quality, and strength. Clinically, a decline inskeletal muscle tissue mass (muscle atrophy) contributes to frailty inolder individuals. In human males, muscle mass declines by one-thirdbetween the ages of 50 and 80. In older adults, extended hospitalizationcan result in further disuse atrophy leading to a potential loss of theability for independent living and to a cascade of physical decline.Moreover, the physical aging process profoundly affects bodycomposition, including significant reductions in lean body mass andincreases in central adiposity. The changes in overall adiposity and fatdistribution appear to be important factors in many common age-relateddiseases such as hypertension, glucose intolerance and diabetes,dyslipidemia, and atherosclerotic cardiovascular disease. In addition,it is possible that the age-associated decrement in muscle mass, andsubsequently in strength and endurance, may be a critical determinantfor functional loss, dependence and disability. Muscle weakness is alsoa major factor prediposing the elderly to falls and the resultingmorbidity and mortality.

The compounds and compositions described and/or disclosed herein may beused to treat cachexia. Cachexia is a state often associated with canceror other serious diseases or conditions, (e.g, chronic obstructivepulmonary disease, heart failure, chronic kidney disease, kidneydialysis), that is characterized by progressive weight loss, muscleatrophy and fatigue, due to the deletion of adipose tissue and skeletalmuscle.

The compounds and compositions described and/or disclosed herein may beused to treat muscular dystrophies. Muscular dystrophy can becharacterized by progressive muscle weakness, destruction andregeneration of the muscle fibers, and eventual replacement of themuscle fibers by fibrous and fatty connective tissue.

The compounds and compositions described and/or disclosed herein may beused to treat post-surgical muscle weakness, which is a reduction in thestrength of one or more muscles following surgical procedure. Weaknessmay be generalized (i.e. total body weakness) or localized to a specificarea, side of the body, limb, or muscle.

The compounds and compositions described and/or disclosed herein may beused to treat post-traumatic muscle weakness, which is a reduction inthe strength of one or more muscles following a traumatic episode (e.g.bodily injury). Weakness may be generalized (i.e. total body weakness)or localized to a specific area, side of the body, limb, or muscle.

The compounds and compositions described and/or disclosed herein may beused to treat muscle weakness and fatigue produced by peripheralvascular disease (PVD) or peripheral artery disease (PAD). Peripheralvascular disease is a disease or disorder of the circulatory systemoutside of the brain and heart. Peripheral artery disease (PAD), alsoknown as peripheral artery occlusive disease (PAOD), is a form of PVD inwhich there is partial or total blockage of an artery, usually oneleading to a leg or arm. PVD and/or PAD can result from, for example,atherosclerosis, inflammatory processes leading to stenosis,embolus/thrombus formation, or damage to blood vessels due to disease(e.g., diabetes), infection or injury. PVD and/or PAD can cause eitheracute or chronic ischemia, typically of the legs. The symptoms of PVDand/or PAD include pain, weakness, numbness, or cramping in muscles dueto decreased blood flow (claudication), muscle pain, ache, cramp,numbness or fatigue that occurs during exercise and is relieved by ashort period of rest (intermittent claudication), pain while resting(rest pain) and biological tissue loss (gangrene). The symptoms of PVDand/or PAD often occur in calf muscles, but symptoms may also beobserved in other muscles such as the thigh or hip. Risk factors for PVDand/or PAD include age, obesity, sedentary lifestyle, smoking, diabetes,high blood pressure, and high cholesterol (i.e., high LDL, and/or hightriglycerides and/or low HDL). People who have coronary heart disease ora history of heart attack or stroke generally also have an increasedfrequency of having PVD and/or PAD. Activators of the fast skeletaltroponin complex have been shown to reduce muscle fatigue and/or toincrease the overall time to fatigue in in vitro and in situ models ofvascular insufficiency (see, e.g., Russell et al., “The Fast SkeletalTroponin Activator, CK-2017357, Increases Skeletal Muscle Force andReduces Muscle Fatigue in vitro and in situ”, 5th Cachexia Conference,Barcelona, Spain, December 2009; Hinken et al., “The Fast SkeletalTroponin Activator, CK-2017357, Reduces Muscle Fatigue in an in situModel of Vascular Insufficiency”, Society for Vascular Medicine's 2010Annual Meeting: 21st Annual Scientific Sessions, Cleveland, Ohio, April2010).

The compounds and compositions described and/or disclosed herein may beused to treat symptoms of frailty, e.g., frailty associated with aging.Frailty is characterized by one or more of unintentional weight loss,muscle weakness, slow walking speed, exhaustion, and low physicalactivity.

The compounds and compositions described and/or disclosed herein may beused to treat muscle weakness and/or fatigue due to wasting syndrome,which is a condition characterized by involuntary weight loss associatedwith chronic fever and diarrhea. In some instances, patients withwasting syndrome lose 10% of baseline body weight within one month.

The compounds and compositions described and/or disclosed herein may beused to treat muscular diseases and conditions caused by structuraland/or functional abnormalities of skeletal muscle tissue, includingmuscular dystrophies, congenital muscular dystrophies, congenitalmyopathies, distal myopathies, other myopathies (e.g., myofibrillar,inclusion body), myotonic syndromes, ion channel muscle diseases,malignant hyperthermias, metabolic myopathies, congenital myasthenicsyndromes, sarcopenia, muscle atrophy and cachexia.

The compounds and compositions described and/or disclosed herein alsomay be used to treat diseases and conditions caused by muscledysfunction originating from neuronal dysfunction or transmission,including amyotrophic lateral sclerosis, spinal muscular atrophies,hereditary ataxias, hereditary motor and sensory neuropathies,hereditary paraplegias, stroke, multiple sclerosis, brain injuries withmotor deficits, spinal cord injuries, Alzheimer's disease, Parkinson'sdisease with motor deficits, myasthenia gravis and Lambert-Eatonsyndrome.

The compounds and compositions described and/or disclosed herein alsomay be used to treat diseases and conditions caused by CNS, spinal cordor muscle dysfunction originating from endocrine and/or metabolicdysregulation, including claudication secondary to peripheral arterydisease, hypothyroidism, hyper- or hypo-parathyroidism, diabetes,adrenal dysfunction, pituitary dysfunction and acid/base imbalances.

The compounds and compositions described and/or disclosed herein may beadministered alone or in combination with other therapies and/ortherapeutic agents useful in the treatment of the aforementioneddisorders.

The compounds and compositions described and/or disclosed herein may becombined with one or more other therapies to treat ALS. Examples ofsuitable therapies include riluzole, baclofen, diazepam, trihexyphenidyland amitriptyline. In some embodiments, the compounds and compositionsdescribed and/or disclosed herein are combined with riluzole to treat asubject suffering from ALS.

The compounds and compositions described and/or disclosed herein may becombined with one or more other therapies to treat myasthenia gravis.Examples of suitable therapies include administration ofanticholinesterase agents (e.g., neostigmine, pyridostigmine), whichhelp improve neuromuscular transmission and increase muscle strength;administration of immunosuppressive drugs (e.g., prednisone,cyclosporine, azathioprine, mycophenolate mofetil) which improve musclestrength by suppressing the production of abnormal antibodies;thymectomy (i.e., the surgical removal of the thymus gland, which oftenis abnormal in myasthenia gravis patients); plasmapheresis; andintravenous immune globulin.

The compounds and compositions described and/or disclosed herein may becombined with one or more other therapies to treat PVD or PAD (e.g.,claudication). Treatment of PVD and PAD is generally directed toincreasing arterial blood flow, such as by smoking cessation,controlling blood pressure, controlling diabetes, and exercising.Treatment can also include medication, such as medicines to help improvewalking distance (e.g., cilostazol, pentoxifylline), antiplatelet agents(e.g., aspirin, ticlopidine, clopidogrel), anticoagulents (e.g.,heparin, low molecular weight heparin, warfarin, enoxaparin)throbmolytics, antihypertensive agents (e.g., diuretics, ACE inhibitors,calcium channel blockers, beta blockers, angiotensin II receptorantagonists), and cholesterol-lowering agents (e.g., statins). In somepatients, angioplasty, stenting, or surgery (e.g., bypass surgery orsurgery to remove an atherosclerotic plaque) may be necessary.

Suitable therapeutic agents include, for example, anti-obesity agents,anti-sarcopenia agents, anti-wasting syndrome agents, anti-frailtyagents, anti-cachexia agents, anti-muscle spasm agents, agents againstpost-surgical and post-traumatic muscle weakness, and anti-neuromusculardisease agents.

Suitable additional therapeutic agents include, for example: orlistat,sibramine, diethylpropion, phentermine, benzaphetamine, phendimetrazine,estrogen, estradiol, levonorgestrel, norethindrone acetate, estradiolvalerate, ethinyl estradiol, norgestimate, conjugated estrogens,esterified estrogens, medroxyprogesterone acetate, testosterone,insulin-derived growth factor, human growth hormone, riluzole,cannabidiol, prednisone, albuterol, non-steroidal anti-inflammatorydrugs, and botulinum toxin.

Other suitable therapeutic agents include TRH, diethylstilbesterol,theophylline, enkephalins, E series prostaglandins, compounds disclosedin U.S. Pat. No. 3,239,345 (e.g., zeranol), compounds disclosed in U.S.Pat. No. 4,036,979 (e.g., sulbenox), peptides disclosed in U.S. Pat. No.4,411,890, growth hormone secretagogues such as GHRP-6, GHRP-1(disclosed in U.S. Pat. No. 4,411,890 and publications WO 89/07110 andWO 89/07111), GHRP-2 (disclosed in WO 93/04081), NN703 (Novo Nordisk),LY444711 (Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, growthhormone releasing factor and its analogs, growth hormone and its analogsand somatomedins including IGF-1 and IGF-2, alpha-adrenergic agonists,such as clonidine or serotonin 5-HT_(D) agonists, such as sumatriptan,agents which inhibit somatostatin or its release, such as physostigmine,pyridostigmine, parathyroid hormone, PTH(1-34), and bisphosphonates,such as MK-217 (alendronate).

Still other suitable therapeutic agents include estrogen, testosterone,selective estrogen receptor modulators, such as tamoxifen or raloxifene,other androgen receptor modulators, such as those disclosed in Edwards,J. P. et. al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L.G. et. al., J. Med. Chem., 42, 210-212 (1999), and progesterone receptoragonists (“PRA”), such as levonorgestrel, medroxyprogesterone acetate(MPA).

Other suitable therapeutic agents include anabolic agents, such asselective androgen receptor modulators (SARMs); antagonists of theactivin receptor pathway, such as anti-myostatin antibodies or solubleactivin receptor decoys, including ACE-031 (Acceleron Pharmaceuticals, asoluble activin receptor type IIB antagonist), MYO-027/PFE-3446879(Wyeth/Pfizer, an antibody myostatin inhibitor), AMG-745 (Amgen, apeptibody myostatin inhibitor), and an ActRIIB decoy receptor (see Zhouet al., Cell, 142, 531-543, Aug. 20, 2010); and anabolic steroids.

Still other suitable therapeutic agents include aP2 inhibitors, such asthose disclosed in U.S. Pat. No. 6,548,529, PPAR gamma antagonists, PPARdelta agonists, beta 3 adrenergic agonists, such as AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer), other beta 3agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134,5,776,983 and 5,488,064, a lipase inhibitor, such as orlistat or ATL-962(Alizyme), a serotonin (and dopamine) reuptake inhibitor, such assibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), athyroid receptor beta drug, such as a thyroid receptor ligand asdisclosed in WO 97/21993, WO 99/00353, and GB98/284425, and anorecticagents, such as dexamphetamine, phentermine, phenylpropanolamine ormazindol.

Still other suitable therapeutic agents include HIV and AIDS therapies,such as indinavir sulfate, saquinavir, saquinavir mesylate, ritonavir,lamivudine, zidovudine, lamivudine/zidovudine combinations, zalcitabine,didanosine, stavudine, and megestrol acetate.

Still other suitable therapeutic agents include antiresorptive agents,hormone replacement therapies, vitamin D analogues, elemental calciumand calcium supplements, cathepsin K inhibitors, MMP inhibitors,vitronectin receptor antagonists, Src SH.sub.2 antagonists, vacuolarH⁺-ATPase inhibitors, ipriflavone, fluoride, Tibo lone, pro stanoids,17-beta hydroxysteroid dehydrogenase inhibitors and Src kinaseinhibitors.

The above therapeutic agents, when employed in combination with thecompounds and compositions disclosed and/or described herein, may beused, for example, in those amounts indicated in the Physicians' DeskReference (PDR) or as otherwise determined by one of ordinary skill inthe art.

The compounds and compositions disclosed and/or described herein areadministered at a therapeutically effective dosage, e.g., a dosagesufficient to provide treatment for the disease state. While humandosage levels have yet to be optimized for the chemical entitiesdescribed herein, generally, a daily dose ranges from about 0.05 to 100mg/kg of body weight; in some embodiments, from about 0.10 to 10.0 mg/kgof body weight, and in some embodiments, from about 0.15 to 1.0 mg/kg ofbody weight. Thus, for administration to a 70 kg person, in someembodiments, the dosage range would be about from 3.5 to 7000 mg perday; in some embodiments, about from 7.0 to 700.0 mg per day, and insome embodiments, about from 10.0 to 100.0 mg per day. The amount of thechemical entity administered will be dependent, for example, on thesubject and disease state being treated, the severity of the affliction,the manner and schedule of administration and the judgment of theprescribing physician. For example, an exemplary dosage range for oraladministration is from about 70 mg to about 700 mg per day, and anexemplary intravenous administration dosage is from about 70 mg to about700 mg per day, each depending upon the compound pharmacokinetics.

Administration of the compounds and compositions disclosed and/ordescribed herein can be via any accepted mode of administration fortherapeutic agents including, but not limited to, oral, sublingual,subcutaneous, parenteral, intravenous, intranasal, topical, transdermal,intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, orintraocular administration. In some embodiments, the compound orcomposition is administered orally or intravenously. In someembodiments, the compound or composition disclosed and/or describedherein is administered orally.

Pharmaceutically acceptable compositions include solid, semi-solid,liquid and aerosol dosage forms, such as tablet, capsule, powder,liquid, suspension, suppository, and aerosol forms. The compoundsdisclosed and/or described herein can also be administered in sustainedor controlled release dosage forms (e.g., controlled/sustained releasepill, depot injection, osmotic pump, or transdermal (includingelectrotransport) patch forms) for prolonged timed, and/or pulsedadministration at a predetermined rate. In some embodiments, thecompositions are provided in unit dosage forms suitable for singleadministration of a precise dose.

The compounds disclosed and/or described herein can be administeredeither alone or in combination with one or more conventionalpharmaceutical carriers or excipients (e.g., mannitol, lactose, starch,magnesium stearate, sodium saccharine, talcum, cellulose, sodiumcrosscarmellose, glucose, gelatin, sucrose, magnesium carbonate). Ifdesired, the pharmaceutical composition can also contain minor amountsof nontoxic auxiliary substances such as wetting agents, emulsifyingagents, solubilizing agents, pH buffering agents and the like (e.g.,sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitanmonolaurate, triethanolamine acetate, triethanolamine oleate).Generally, depending on the intended mode of administration, thepharmaceutical composition will contain about 0.005% to 95%, or about0.5% to 50%, by weight of a compound disclosed and/or described herein.Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

In some embodiments, the compositions will take the form of a pill ortablet and thus the composition may contain, along with a compoundsdisclosed and/or described herein, one or more of a diluent (e.g.,lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesiumstearate), and/or a binder (e.g., starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Othersolid dosage forms include a powder, marume, solution or suspension(e.g., in propylene carbonate, vegetable oils or triglycerides)encapsulated in a gelatin capsule.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing or suspending etc. a compounddisclosed and/or described herein and optional pharmaceutical additivesin a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols,ethanol or the like) to form a solution or suspension. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, as emulsions, or in solid forms suitable for dissolution orsuspension in liquid prior to injection. The percentage of the compoundcontained in such parenteral compositions depends, for example, on thephysical nature of the compound, the activity of the compound and theneeds of the subject. However, percentages of active ingredient of 0.01%to 10% in solution are employable, and may be higher if the compositionis a solid which will be subsequently diluted to another concentration.In some embodiments, the composition will comprise from about 0.2 to 2%of a compound disclosed and/or described herein in solution.

Pharmaceutical compositions of the compounds disclosed and/or describedherein may also be administered to the respiratory tract as an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the pharmaceutical composition may have diametersof less than 50 microns, or in some embodiments, less than 10 microns.

In addition, pharmaceutical compositions can include a compounddisclosed and/or described herein and one or more additional medicinalagents, pharmaceutical agents, adjuvants, and the like. Suitablemedicinal and pharmaceutical agents include those described herein.

The following examples serve to more fully describe the inventiondescribed herein. It is understood that these examples in no way serveto limit the true scope of this invention, but rather are presented forillustrative purposes.

EXAMPLE 1 (S)-2-(4-Fluorophenyl)propan-1-amine

(S)-4-Benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one

To a cooled (−78° C.) solution of (S)-4-benzyloxazolidin-2-one (10 g, 58mmol, 1.0 equiv) in 100 mL THF was added dropwise n-BuLi (40 mL, 1.6 Min hexanes, 64 mmol, 1.1 equiv). After stirring for 30 minutes,4-fluorophenylacetyl chloride (10 g, 0.58 mmol, 1.0 equiv) was addeddropwise. After stirring for an additional 30 minutes, the reactionmixture was allowed to warm to room temperature. The reaction wasquenched with saturated aq. NH₄Cl, extracted with dichloromethane, andwashed with brine. The organic layer was then dried over sodium sulfate,filtered, and concentrated in vacuo. Purification by silica gel (10-20%EtOAc/hexanes) provided the title compound as a thick oil (14.7 g, 81%).

(S)-4-Benzyl-34(S)-2-(4-fluorophenyl)propanoyl)oxazolidin-2-one

To a room-temperature solution of(S)-4-Benzyl-3-(2-(4-fluorophenyl)acetyl)oxazolidin-2-one (5.1 g, 16.3mmol, 1.0 equiv) in dry THF (100 mL) was added iodomethane (1.0 mL, 16.2mmol, 1.0 equiv) by syringe. The resulting mixture was cooled to −78°C., and NaHMDS (8.15 mL, 2M in THF, 16.3 mmol, 1.0 equiv) was addeddropwise by syringe. After stirring for 15 minutes at −78° C., thereaction mixture was allowed to warm to room temperature. The reactionwas quenched with saturated. aq. NH₄Cl, and diluted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (7-20%EtOAc/hexanes) provided the title compound (2.6 g, 49%).

(S)-2-(4-Fluorophenyl)propan-1-ol

To a room-temperature solution of (S)-4-benzyl-3-((S)-2-(4-fluorophenyl)propanoyl)oxazolidin-2-one (1.8 g, 5.5 mmol, 1.0 equiv) in THF (18 mL)was added a solution of NaBH₄ (1.0 g, 26.4 mmol, 4.8 equiv) in water(6.0 mL). The reaction mixture was stirred for 3 h at room temperatureand then quenched by the careful addition of aq. 1 M HCl. The reactionmixture was diluted with water and ethyl acetate. The layers wereseparated and the organic layer was subsequently washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. Purification bysilica gel chromatography (10-75% EtOAc/Hexanes) provided the titlecompound (0.824 g, 97%).

(S)-2-(2-(4-Fluorophenyl)propyl)isoindoline-1,3-dione

To a solution of (S)-2-(4-fluorophenyl)propan-1-ol (0.82 g, 5.35 mmol,1.0 equiv), phthalimide (0.82 g, 5.6 mmol, 1.05 equiv), and triphenylphosphine (2.1 g, 8.03 mmol, 1.5 equiv) in dry THF (18 mL) was addeddropwise diethylazodicarboxylate (3.6 mL, 15% in toluene, 8.0 mmol, 1.5equiv). The reaction mixture was stirred over 72 h and then concentratedin vacuo. Purification by silica gel chromatography (15-25%EtOAc/Hexanes) provided the title compound (0.9 g, 59%).

(S)-2-(4-Fluorophenyl)propan-1-amine

To a room-temperature solution of(S)-2-(2-(4-fluorophenyl)propyl)isoindoline-1,3-dione (900 mg, 3.2 mmol,1.0 equiv) in toluene (14 mL) was added hydrazine hydrate (1.4 mL, 45mmol, 14 equiv) by syringe. The resulting mixture was heated to 80° C.for 30 minutes and then cooled to room temperature. The resultingsolution was decanted from the solid in the reaction mixture, and thesolid was washed with additional toluene. The combined organic layerswere combined and concentrated in vacuo to provide the title compound(491 mg, 99%), which was used without further purification.

EXAMPLE 2 2-(4-Fluorophenyl)-2-methylpropan-1-amine

To a solution of 4-fluorophenylacetonitrile (50 g, 370 mmol, 1.0 equiv)and iodomethane (70 mL, 1.1 mol, 3 equiv) in THF (370 mL) was addedKOt-Bu (124 g, 1.1 mol, 3 equiv) as a solid in portions such that thereaction mixture did not exceed 50° C. The reaction mixture was stirredovernight and then quenched by the addition of brine. The mixture wasdiluted with EtOAc and washed twice with brine. The organic layer wasdried over Na₂SO₄, filtered, and concentrated in vacuo to provide2-(4-fluorophenyl)-2-methylpropanenitrile as a yellow oil (57 g, 94%),which was used without further purification in the next step. To asolution of the nitrile in dry THF (800 mL) was added a solution oflithium aluminum hydride (210 mL, 2 M in ether, 420 mmol, 1.2 equiv).After the mixture was heated at reflux overnight, the reaction wasallowed to cool to room temperature, and a Fieser and Fieser work-up(300 uL water/mmol, 1.0 mL 3N NaOH/mmol, 300 uL water/mmol) wasperformed. Filtration of the resulting solids provided the titlecompound as an orange oil (57 g, 92%).

EXAMPLE 3 (1-(4-Fluorophenyl)cyclobutyl)methanamine

A solution of 4-fluorophenylacetonitrile (6.7 g, 75 mmol, 1.5 equiv),1,3-dibromopropane (10 mL, 50 mmol, 1 equiv), KOH (27 g, 150 mmol, 3.0equiv), and tetrabutylammonium bromide (100 mg) in toluene (135 mL) washeated to 100° C. for 3 hours. The organic layer was separated andconcentrated to dryness. Silica gel chromatography using a gradient of0-30% EtOAc/hexanes resulted in partially purified product which wasfurther purified by Kugelrohr distillation at 200° C. to provide 3.76 g(22 mmol) of the intermediate nitrile product as an oil. The residue wasdissolved in dry THF (22 mL) and treated with a solution of lithiumaluminum hydride (27 mL, 2 M in ether, 55 mmol, 2.5 equiv). The mixturewas stirred at 0° C. for 2 hours followed by a Fieser and Fieser work-up(38 uL water/mmol, 118 uL 3N NaOH/mmol, 38 uL water/mmol). The organiclayer was concentrated to dryness to provide the desired product (3.6 g,40% overall) as a yellow oil.

EXAMPLE 4 (1-(6-Methoxypyridin-2-yl)cyclobutyl)methanamine

2-(3-Fluoropyridin-2-yl)acetonitrile

To a 0° C. solution of 2-chloro-3-fluoropyridine (3.0 g, 23 mmol, 1.0equiv) and acetonitrile (1.3 mL, 25 mmol, 1.1 equiv) in toluene (50 mL)was added sodium hexamethyldisilazide (NaHMDS) (2.0 M in THF, 13 mL, 25mmol, 1.1 equiv). The resulting mixture was stirred for 2 hours at 0° C.and then partitioned between EtOAc and water. The aqueous layer wasextracted with EtOAc and the combined organic phases were washed withsaturated NaCl, dried over Na₂SO₄ and concentrated in vacuo to providethe crude desired product as an oil which was used without furtherpurification.

1-(6-Fluoropyridin-2-yl)cyclobutanecarbonitrile

Following the same procedure as above for2-(3-fluoropyridin-2-yl)acetonitrile with 2,6-difluoropyridine (5.0 g,43 mmol, 1.0 equiv), cyclobutylcarbonitrile (3.5 g, 43 mmol, 1.0 equiv)and NaHMDS (2.0 M in THF, 24 mL, 47 mmol, 1.1 equiv) in toluene (100 mL)gave the desired product (4.9 g, 64%) as a colorless oil followingpurification over silica gel using 25% EtOAc/hexanes as eluent.

1-(6-Methoxypyridin-2-yl)cyclobutanecarbonitrile

To stirred 6.0 mL of anhydrous methanol at 0° C. under nitrogen wasadded sodium metal (˜1 g) and the mixture stirred for 30 minutes. Tothis was added 1-(6-fluoropyridin-2-yl)cyclobutanecarbonitrile (1.6 g,9.1 mmol, 1.0 equiv) and the resulting mixture heated to 75° C. for 45minutes. The solution was cooled to room temperature and partitionedbetween water and EtOAc. The layers were separated, the aqueous phasewas extracted with EtOAc, and the combined organic phases were washedwith saturated NaCl, dried over Na₂SO₄ and concentrated in vacuo to givethe desired product (1.7 g, 97%) as a colorless oil.

(1-(6-Methoxypyridin-2-yl)cyclobutyl)methanamine

To a stirred solution of1-(6-methoxypyridin-2-yl)cyclobutanecarbonitrile (1.7 g, 8.8 mmol, 1.0equiv) in THF (20 mL) was added lithium aluminum hydride solution (1.0 Min THF, 11 mL, 11 mmol, 1.1 equiv). The mixture was refluxed for 1.5hours and allowed to cool to room temperature. Water (0.43 mL) was addedslowly followed by 0.43 mL of 3 M NaOH and then three additions of 0.43mL of water (Fieser and Fieser workup). The resulting mixture wasfiltered through diatomaceous earth and rinsed with THF. The combinedorganics were dried over Na₂SO₄ and concentrated to dryness to give thedesired product (1.6 g, 97%) as a viscous oil.

EXAMPLE 5 1-(3-Fluoropyridin-2-yl)cyclobutanamine

1-(3-Fluoropyridin-2-yl)cyclobutanecarboxamide

To a 250 mL round bottom flask containing DMSO (60 mL),1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (2.96 g, 16.8 mmol, 1.0equiv) was added and the mixture was stirred until homogenous. Potassiumcarbonate (7.0 g, 50.4 mmol, 3.0 equiv) was then added and the reactionmixture was cooled to 0° C., followed by the addition of 35% hydrogenperoxide (6.5 mL). The reaction was stirred at 0° C. for 30 min and thenwarmed to room temperature. At this time, the reaction was diluted withwater (50 mL) and ethyl acetate (100 mL). After transferring to aseparatory funnel and shaking, the organic layer was separated from theaqueous layer and then washed with brine (3×50 mL). The organic layerwas then dried over Na₂SO₄, filtered, and concentrated to give a crudesolid that was purified by silica gel chromatography (10% EtOAC/hexanes)to afford 1.92 g (59%) of 1-(3-fluoropyridin-2-yl)cyclobutanecarboxamideas a white solid.

Methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate

1-(3-fluoropyridin-2-yl)cyclobutanecarboxamide (1.92 g, 9.88 mmol, 1.0equiv) was dissolved in methanol (20 mL) and potassium hydroxide (1.11g, 19.8 mmol, 2.0 equiv) was added. The mixture was sonicated untilhomogeneous, followed by the addition of iodosobenzene diacetate (4.77g, 14.8 mmol, 1.5 equiv). The reaction was stirred for 20 min and thendiluted with water (100 mL) and ethyl acetate (125 mL). Aftertransferring to a separatory funnel and shaking, the organic layer wasseparated from the aqueous layer, and the aqueous layer was extractedwith EtOAc (50 mL). The combined organic layers were then dried overNa₂SO₄, filtered, and concentrated to give a crude oil that was purifiedby silica gel chromatography (40% EtOAC/hexanes) to afford 1.47 g (67%)of methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate as a white solid.

1-(3-Fluoropyridin-2-yl)cyclobutanamine

To a 20 mL microwave reaction vial was added methyl1-(3-fluoropyridin-2-yl)cyclobutylcarbamate (1.47 g, 6.56 mmol, 1.0equiv), ethanol (12 mL) and 3N aqueous sodium hydroxide (7 mL). Thereaction mixture was heated in the microwave reactor at 150° C. for 30min. The ethanol was evaporated under reduced pressure and the mixturewas extracted with ethyl acetate (30 mL). The aqueous layer was thenextracted with ethyl acetate (2×30 mL). The organic layers werecombined, dried over Na₂SO₄, filtered, and concentrated to give1-(3-fluoropyridin-2-yl)cyclobutanamine (1.01 g, 93%) as a crude yellowoil that was used without further purification.

EXAMPLE 6N-(2-(4-Fluorophenyl)-2-methylpropyl)-6-(2-methylprop-1-enyl)pyridin-2-amine

6-Bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine

To a 5 mL microwave reaction vial was added 2,6-dibromopyridine (1.25 g,5.0 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (1.06 g,6 mmol, 1.2 equiv), DIPEA (1.9 mL, 11.0 mmol, 2.2 equiv), andacetonitrile (5 mL). The vial was sealed and heated in an oil bath at137° C. for 48 h, concentrated, and purified by silica gel columnchromatography to give 220 mg (14%) of6-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine as a whitesolid (m/z [M+H]=323).

N-(2-(4-Fluorophenyl)-2-methylpropyl)-6-(2-methylprop-1-enyl)pyridin-2-amine

To a 5 mL microwave reaction vessel was added6-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine (220 mg,0.7 mmol, 1.0 equiv), 2-methylprop-1-enylboronic acid (100 mg, 1 mmol,1.5 equiv), Cl₂Pd(dppf) (50 mg, 70 μmol, 0.1 equiv), potassium carbonate(300 mg, 2.1 mmol, 3.0 equiv), dioxane (4 mL), and water (1 mL). Thereaction was heated in a microwave reactor at 135° C. for 35 min andthen diluted with saturated sodium bicarbonate (20 mL) and extractedwith ethyl acetate (50 mL). The organic layer was then dried overNa₂SO₄, filtered, and concentrated to give a crude solid that waspurified by reverse phase column chromatography to afford 14 mg ofN-(2-(4-fluorophenyl)-2-methylpropyl)-6-(2-methylprop-1-enyl)pyridin-2-amine(m/z [M+H]=299.4).

EXAMPLE 7 4-Phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine

4-Bromo-N-(1-phenylcyclobutyl)pyridin-2-amine

To a 20 dram vial was added 4-bromo-2-chloropyridine (250 mg, 5.0 mmol,1.0 equiv), 1-phenylcyclobutanamine (1.0 g, 7 mmol, 1.4 equiv), and NMP(1 mL). The reaction was heated to 120° C., stirred for 72 h, and thendiluted with water (20 mL) and ethyl acetate (50 mL). After transferringto a separatory funnel and shaking, the organic layer was separated fromthe aqueous layer. The organic layer was then dried over Na₂SO₄,filtered, and concentrated to give a crude solid that was purified bysilica gel column chromatography, affording 139 mg (9%) of4-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine as an orange solid.

4-Phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine

To a 3 mL microwave reaction vessel was added4-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine (50 mg, 165 μmol, 1.0equiv), phenylboronic acid (30 mg, 248 μmol, 1.5 equiv), Cl₂Pd(dppf) (12mg, 16 μmol, 0.1 equiv), potassium carbonate (57 mg, 413 μmol, 2.5equiv), dioxane (750 μL), and water (250 μL). The reaction was heated ina microwave reactor at 140° C. for 20 min and then diluted withsaturated sodium bicarbonate (20 mL) and extracted with ethyl acetate(50 mL). The organic layer was then dried over Na₂SO₄, filtered, andconcentrated to give a crude solid that was purified by reverse phasecolumn chromatography to afford 9 mg of4-phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine (m/z [M+H]=301.2).

EXAMPLE 8 5-Phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine

5-Bromo-N-(1-phenylcyclobutyl)pyridin-2-amine

To a 20 dram vial was added 5-bromo-2-fluoropyridine (250 mg, 5.0 mmol,1.0 equiv), 1-phenylcyclobutanamine (1.0 g, 7 mmol, 1.4 equiv), and NMP(1 mL). The reaction was heated to 120° C., stirred for 72 h, and thendiluted with water (20 mL) and extracted with ethyl acetate (50 mL). Theorganic layer was then dried over Na₂SO₄, filtered, and concentrated togive a crude solid that was purified by silica gel column chromatographyto give 102 mg (26%) of 5-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine asa pale yellow solid.

5-Phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine

To a 3 mL microwave reaction vessel was added5-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine (102 mg, 340 μmol, 1.0equiv), phenylboronic acid (59 mg, 505 μmol, 1.5 equiv), Cl₂Pd(dppf) (25mg, 34 μmol, 0.1 equiv), potassium carbonate (116 mg, 842 μmol, 2.5equiv), dioxane (1 mL) and water (500 μL). The reaction was heated in amicrowave reactor at 140° C. for 20 min and then diluted with saturatedsodium bicarbonate (20 mL) and extracted with ethyl acetate (50 mL). Theorganic layer was then dried over Na₂SO₄, filtered, and concentrated togive a crude solid that was purified by silica gel column chromatography(10% EtOAc/hexanes), affording 27 mg of5-phenyl-N-(1-phenylcyclobutyl)pyridin-2-amine as a white solid (m/z[M+H]=301.2).

EXAMPLE 91-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethane-1,2-diol

N-(2-(4-Fluorophenyl)-2-methylpropyl)-5-vinylpyridin-2-amine

To a 5 mL microwave reaction vessel was added5-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine (255 mg,0.8 mmol, 1.0 equiv), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (285mg, 1.2 mmol, 1.5 equiv), Cl₂Pd(dppf) (58 mg, 79 μmol, 0.1 equiv),potassium carbonate (1.2 mL of a 2N aqueous solution, 2.4 mmol, 3.0equiv), and dioxane (4 mL). The reaction was heated in a microwavereactor at 115° C. for 20 min. The aqueous layer was removed from thereaction, and the organic layer was directly purified by reverse phasecolumn chromatography to give 158 mg (73%) ofN-(2-(4-fluorophenyl)-2-methylpropyl)-5-vinylpyridin-2-amine.

1-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethane-1,2-diol

N-(2-(4-fluorophenyl)-2-methylpropyl)-5-vinylpyridin-2-amine (158 mg,0.6 mmol, 1.0 equiv) was added to a foil-covered 20 dram vial and thendissolved in a 50% THF/water mixture (6 mL). Osmium tetraoxide (15 mg,0.06 mmol, 0.1 equiv) and morpholine N-oxide (103 mg, 0.9 mmol, 1.5equiv) were added, and the reaction was stirred for 1 h. Additional THF(3 mL) was added, and the reaction was stirred for 3 h. The reactionmixture was then diluted with water (10 mL) and extracted with ethylacetate (30 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated to give a crude solid that was purified by reverse phasecolumn chromatography to give 129 mg (86%) of1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethane-1,2-diol(m/z [M+H]=305).

EXAMPLE 10N-(2-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethyl)-methanesulfonamide

tert-Butyl2-(4-fluorophenyl)-2-methylpropyl(5-(2-hydroxyethyl)pyridin-2-yl)carbamate

To a 20 dram vial was added tert-butyl2-(4-fluorophenyl)-2-methylpropyl(5-vinylpyridin-2-yl)carbamate (2.4 g,6.4 mmol, 1.0 equiv) and THF (20 mL). Borane (7.7 mL, 7.7 mmol, 4.0equiv) was added slowly, and the reaction was heated to 35° C. andstirred for 45 min. The reaction was then cooled to 0° C. followed bythe addition of a 50% ethanol/THF mixture (25 mL), 2N sodium hydroxide(13 mL, 25.8 mmol, 4.0 equiv), and 30% hydrogen peroxide (15 mL). Thereaction was stirred for 1 h, diluted with brine (10 mL), and extractedwith ethyl acetate (20 mL). The organic layer was dried over Na₂SO₄,filtered, concentrated, and then purified by reverse phase columnchromatography to give 414 mg (17%) of tert-butyl2-(4-fluorophenyl)-2-methylpropyl(5-(2-hydroxyethyl)pyridin-2-yl)carbamate.

tert-Butyl-5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)-carbamate

Methanesulfonyl chloride (87 μL, 1.1 mmol, 1.1 equiv) dissolved in 2 mLethyl acetate was added to a 20 dram vial. To this stirring mixture wasadded a mixture oftert-butyl-2-(4-fluorophenyl)-2-methylpropyl(5-(2-hydroxyethyl)pyridin-2-yl)-carbamate(414 mg, 1.1 mmol, 1.0 equiv), TMEDA (167 μL, 1.1 mmol, 1.1 equiv), andethyl acetate (3 mL) in a dropwise manner. The reaction was stirred for1 h. The reaction mixture was then filtered and washed with saturatedsodium bicarbonate and brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated. The resultant solid was dissolved in DMF (4mL), followed by the addition of sodium azide (139 mg, 2.1 mmol, 2.0equiv). The reaction was stirred for 24 h, then diluted with water (10mL) and extracted with ethyl acetate (20 mL). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The crude solid wasdissolved in methanol, followed by the addition of 10% palladium oncarbon (80 mg), potassium carbonate (100 mg). The reaction was stirredunder 45 psi of hydrogen for 24 h, filtered, and concentrated to givetert-butyl5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate.

N-(2-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethyl)-methanesulfonamide

To a 20 dram vial was added tert-butyl5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate(140 mg, 0.34 mmol, 1.0 equiv), TEA (87 μL, 0.67 mmol, 2.0 equiv, THF (3mL), and methanesulfonyl chloride (29 μL, 0.37 mmol, 1.1 equiv). Thereaction was stirred for 2 h and then concentrated, followed by theaddition of MeOH (1 mL) and 4N HCl/dioxane (3 mL). The reaction wasstirred for 1 h, concentrated, and then purified by preparative TLC (5%MeOH/CH₂Cl₂) to give 5 mg ofN-(2-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)ethyl)-methanesulfonamide(m/z [M+H]=366).

EXAMPLE 11 6-(2-(4-Fluorophenyl)-2-methylpropylamino)nicotinamide

6-(2-(4-Fluorophenyl)-2-methylpropylamino)nicotinonitrile

To a solution of 6-chloronicotinonitrile (200 mg, 1.46 mmol, 1.0 equiv)and 2-(4-fluorophenyl)-2-methylpropan-1-amine (290 mg, 1.75 mmol, 1.2equiv) in isopropanol (3 mL) in a microwave vial equipped with a stirbar was added potassium carbonate (720 mg, 2.19 mmol, 1.5 equiv). Thevial was fitted with a microwave vial cap and heated to 120° C. for 20min. The reaction mixture was filtered to remove the solid potassiumcarbonate and concentrated in vacuo. After the residue was redissolvedin EtOAc and water, the organic layer was washed with brine, dried oversodium sulfate, and concentrated in vacuo. Purification by silica gelchromatography (1%-3% MeOH/DCM) provided the title compound as a beigesolid (104 g, 27%), (m/z [M+H]=270.1).

6-(2-(4-Fluorophenyl)-2-methylpropylamino)nicotinamide

To a cooled (0° C.) suspension of6-(2-(4-fluorophenyl)-2-methylpropylamino)nicotinonitrile (75 mg, 0.28mmol, 1.0 equiv) and K₂CO₃ (50 mg, 0.36 mmol, 1.3 equiv) in DMSO (1 mL)was added aq. H₂O₂ (250 uL, 30% by wt., 2.6 mmol, 9 equiv) by syringe.The reaction was allowed to warm to RT and stirred for 30 minutes. Theresulting mixture was diluted with EtOAc and washed three times withsatd. aq. LiCl and once with brine. The resulting solution was driedover sodium sulfate, filtered, and concentrated in vacuo. Purificationby silica gel chromatography (2%-10% MeOH/DCM) provided the titlecompound as an off-white foam (54 mg, 77%), (m/z [M+H]=288.1).

EXAMPLE 12Methyl(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)methylcarbamate

5-(Aminomethyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine

To a 100 mL round bottom flask was added6-(2-(4-fluorophenyl)-2-methylpropylamino)nicotinonitrile (1.0 g, 3.7mmol, 1.0 equiv) and THF (15 mL), followed by the addition of 1M lithiumaluminum hydride/THF (14.8 mL, 14.8 mmol, 4.0 equiv). The reaction washeated to reflux for 3 h and allowed to cool to rt. The reaction mixturewas then quenched by the sequential slow addition water (0.6 mL), 3NNaOH (0.6 mL), and water (1.7 mL). The resultant precipitate wasfiltered and the filtrate was then dried (Na₂SO₄) and concentrated togive 1.0 g (99%) of5-(aminomethyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine.

Methyl(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)methylcarbamate

To a 20 dram vial was added5-(aminomethyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine(100 mg, 0.37 mmol, 1.0 equiv), DIPEA (57 mg, 0.44 mmol, 1.2 equiv) andCH₂Cl₂ (1.2 mL). The mixture was cooled to 0° C., and methyl carbamate(35 mg, 0.4 mmol, 1.0 equiv) was then added. The reaction was allowed towarm to rt and stirred for 2 h. The reaction mixture was then dilutedwith water (2 mL) and extracted with ethyl acetate (15 mL). The organiclayer was dried over Na₂SO₄, filtered, and concentrated to give a crudesolid that was purified by silica gel column chromatography, affording20 mg ofmethyl(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridin-3-yl)methylcarbamate(m/z [M+H]=332).

EXAMPLE 13 Preparation of3-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-3-yl)benzamide

Ethyl 2-(3-chlorobenzamido)acetate

To a stirred solution of 3-chlorobenzoyl chloride (6.0 mL, 58 mmol) indichloromethane (150 mL) were added ethyl glycinate hydrochloride (10 g,72 mmol) and triethylamine (20 mL, 142 mmol). After stirring for 1 h,the mixture was diluted with saturated NaHCO₃ and the aqueous layerextracted twice with dichloromethane. The combined organic layers weredried over Na₂SO₄ and evaporated to dryness in vacuo to give the desiredproduct (9.8 g) as a white solid which was taken on withoutpurification.

Ethyl 2-(3-chlorophenylthioamido)acetate

To a stirred solution of ethyl 2-(3-chlorobenzamido)acetate (9.8 g, 40mmol) in toluene (150 mL) was added phosphorus pentasulfide (18 g, 42mmol), and the mixture was heated to 120° C. for 1 h. The mixture wasfiltered, evaporated to dryness, and purified using silica gelchromatography (0-100% EtOAc/hexanes) as eluent gave 7.0 g of crudeproduct which was carried forward without further purification

3-(3-Chlorophenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one

To a solution of ethyl 2-(3-bromophenylthioamido)acetate (˜40 mmol) inethanol (100 mL) was added hydrazine hydrate (5 mL). The mixture washeated to 90° C. for 2 h and allowed to cool to room temperature.Concentration in vacuo gave a yellow solid that was purified over silicagel using 10% MeOH/DCM as eluent to give the desired product (7.0 g) asan off-white solid.

3-(3-Chlorophenyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-6-amine

To a solution of 3-(3-chlorophenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one(6.0 g, 29 mmol) dissolved in dioxane (75 mL) was added MnO₂ (10 g, 120mmol). The mixture was stirred at 90° C. for 18 h. After filteringthrough diatomaceous earth and rinsing with hot dioxane, the combinedorganics were evaporated to dryness in vacuo. The crude residue (⅓ wasused) was dissolved in POCl₃ (10 mL, 108 mmol) and heated to 70° C. for2.5 h. The mixture was allowed to cool to rt and evaporated to drynessin vacuo. The residue was dissolved in EtOAc/ether (1:1) and washed with1 M NaOH. The organic phase was evaporated to dryness and dissolved inNMP (5.0 mL) in a microwave vial. Potassium carbonate (1.0 g) was addedfollowed by (2-(4-fluorophenyl)-2-methylpropan-1-amine (2.0 g, 12 mmol),and the mixture was heated in a microwave reactor to 165° C. for 20 min.The solution was diluted with EtOAc and washed with saturated NaCl (4×),dried over Na₂SO₄, and evaporated to dryness. Purification using silicagel chromatography (0-35% EtOAc/hexanes) gave the desired product (430mg) as an orange film.

3-(6-(2-(4-Fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-3-yl)benzonitrile

To a microwave vial containing NiBr₂ (280 mg, 1.3 mmol) and NaCN (120mg, 2.5 mmol) was added a solution of3-(3-chlorophenyl)-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-6-amine(450 mg, 1.3 mmol) in NMP (4.0 mL). The vial was purged with nitrogenand sealed. The mixture was heated to 200° C. in a microwave for 25 minand allowed to cool to room temperature. The solution was diluted withEtOAc/ether (1:1), washed with water (3×), dried over Na₂SO₄ andevaporated to dryness. Purification using silica gel chromatography(0-65% EtOAc/hexanes) gave the desired product (220 mg) as an off whitefoam.

3-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-3-yl)benzamide

To a solution of3-(6-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-3-yl)benzonitrile(220 mg, 0.60 mmol) in DMSO (3.0 mL) was added K₂CO₃ (300 mg, 2.2 mmol)and 30% hydrogen peroxide (0.60 mL, 7.5 mmol). The mixture was stirred24 h and partitioned between EtOAc and water. The aqueous layer wasextracted with EtOAc (2×) and the combined organics were dried overNa₂SO₄ and evaporated to dryness in vacuo. Purification using silica gelchromatography (0-100% EtOAc/hexanes) gave the desired product (17 mg),m/z=366.1 [M+H].

EXAMPLE 14 Preparation of5-(3-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-6-yl)-1H-indazol-3-amine

3-Amino-1,2,4-triazin-2-oxide

To a solution of 1,2,4-triazin-3-amine (2.8 g, 30 mmol) in CH₃CN (25 mL)was added portionwise mCPBA (14 g, 81 mmol). The mixture was refluxedfor 2 h and then evaporated to dryness. The residue was mixed with etherand filtered to give the desired product as a yellow solid that was usedin the next step without purification.

3-Bromo-1,2,4-triazin-2-oxide

To a solution of 48% (wt/wt) HBr (100 mL) was added1,2,4-triazin-3-amine-2-oxide (30 mmol), and the mixture was stirred atrt. A solution of NaNO₂ (30 g, 430 mmol) in water (40 mL) was addedslowly, and the mixture was stirred for 1 h. The reaction was quenchedby the addition of an excess of saturated NaHCO₃ and extracted withdichloromethane. The combined organic layers were evaporated to dryness.Purification using silica gel chromatography (EtOAc/hexanes) gave 1.3 gof the intermediate bromide product.

N-(2-(4-Fluorophenyl)-2-methylpropyl)-1,2,4-triazin-3-amine-2-oxide

A solution of 3-bromo-1,2,4-triazin-2-oxide (2.0 g, 11 mmol),(2-(4-fluorophenyl)-2-methylpropan-1-amine (3.0 g, 17 mmol), anddiisopropylethylamine (3.0 mL, 17 mmol) in CH₃CN (20 mL) was stirred atrt for 24 h. The solvents were removed and the residue dissolved inEtOAc. The solution was washed with saturated NaHCO₃, dried over Na₂SO₄,and evaporated to dryness. The residue was mixed with ether and thenfiltered to give the desired product (1.2 g) as a yellow solid.

6-Bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-3-amine-2-oxide

To a solution ofN-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-3-amine-2-oxide (1.2g, 7.4 mmol) in a 1:1 mixture of dichloromethane and CH₃CN (40 mL) wasadded Br₂ (1.0 mL, 19 mmol). The mixture was stirred at room temperaturefor 72 h. The solvents were evaporated and the residue was dissolved inether. The solution was filtered through a plug of silica gel and thesolvents evaporated to give the desired product (1.5 g, 58%) as anorange sticky solid.

2-Fluoro-5-(3-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-2-oxide-6-yl)benzonitrile

To a solution of6-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)-1,2,4-triazin-3-amine-2-oxide(0.48 g, 1.4 mmol, 1.0 equiv), 3-cyano-4-fluorophenylboronic acid (0.35g, 2.1 mmol), and K₂CO₃ (0.5 g, 3.6 mmol) in DMF (2 mL) was addedPd(dppf)Cl₂ (0.10 g, 0.13 mmol). The mixture was stirred at 75° C. for 4h and then quenched by addition of excess saturated NaHCO₃. The mixturewas extracted with EtOAc and the organic layer was concentrated.Purification using silica gel chromatography (1-40% EtOAc/hexanes) gavethe desired product (0.38 g) as a yellow solid.

5-(3-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-6-yl)-1H-indazol-3-amine

A stirred solution of2-fluoro-5-(3-(2-(4-fluorophenyl)-2-methylpropylamino)-1,2,4-triazin-2-oxide-6-yl)benzonitrile(0.18 g, 0.47 mmol) and hydrazine (0.1 mL, 2.0 mmol) in n-butanol (0.5mL) was sealed and heated to 119° C. for 1 h. The solvents were removedand the residue dissolved in benzylamine with a minimal amount of CH₃CN.The mixture was sealed and stirred at 177° C. overnight. The mixture wasloaded directly onto a reverse phase HPLC for purification using agradient of CH₃CN/water to give the desired product (28 mg), m/z=378.1[M+H].

EXAMPLE 15 Preparation of4-fluoro-3-(3-(2-(3-fluoropyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)benzamide

6-(5-Bromo-2-fluorophenyl)-1,2,4-triazin-3-amine

6-Bromo-1,2,4-triazin-3-amine (9.1 g, 40.8 mmol),5-bromo-2-fluorophenylboronic acid (98.9 g, 40.8 mmol), (dppf)PdCl₂ (3.0g, 4.0 mmol), nitrogen-sparged dioxane (81.6 mL), and aq. 2 N K₂CO₃ (17mL) were combined and heated in a round bottom flask at 90° C. for 4 h.The hot mixture was filtered through a pad of celite and diluted withEtOAc and washed with water. Concentration followed by trituration withDCM afforded a tan solid (4.5 g), m/z=269.0 [M+H].

3-Bromo-6-(5-bromo-2-fluorophenyl)-1,2,4-triazine

6-(5-Bromo-2-fluorophenyl)-1,2,4-triazin-3-amine (4.5 g, 16.7 mmol) wasdissolved in 25 mL of bromoform and heated to 80° C. Isoamyl nitrite(9.8 g, 83.5 mmol) was then added and stirred at 85° C. for 1 h. Thereaction mixture was then concentrated and silica gel chromatographyafforded a yellow solid (4.4 g), m/z=331.1 [M+H].

6-(5-Bromo-2-fluorophenyl)-N-(2-(2-fluorophenyl)propan-2-yl)-1,2,4-triazin-3-amine

3-Bromo-6-(5-bromo-2-fluorophenyl)-1,2,4-triazine (2.8 g, 8.4 mmol),2-(2-fluorophenyl)propan-2-amine (2.0 g, 12.6 mmol), K₂CO₃ (2.3 g, 16.8mmol) and CH₃CN (20 mL) was heated to 90° C. The reaction mixture wasdiluted with EtOAc and washed with satd. aq. NaHCO₃ and brine. Theorganic layer was dried over sodium sulfate, filtered, concentrated, andpurified using silica gel chromatography to afford a yellow solid (2.3g), m/z=406.1 [M+H].

4-Fluoro-3-(3-(2-(2-fluorophenyl)propan-2-ylamino)-1,2,4-triazin-6-yl)benzonitrile

6-(5-Bromo-2-fluorophenyl)-N-(2-(2-fluorophenyl)propan-2-yl)-1,2,4-triazin-3-amine(2.2 g, 5.6 mmol), zinc cyanide (0.72 g, 6.2 mmol), Pd(PPh₃)₄ (2.9 g,2.8 mmol), and DMF (20 mL) were combined and heated in a round bottomflask at 100° C. for 2 h. The reaction mixture was diluted with EtOAcand washed with satd. aq. NaHCO₃ and brine. The organic layer was driedover sodium sulfate, filtered, concentrated and purified using silicagel chromatography to provide a yellow solid (1.7 g), m/z=352.1 [M+H].

4-Fluoro-3-(3-(2-(3-fluoropyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)benzamide

4-Fluoro-3-(3-(2-(2-fluorophenyl)propan-2-ylamino)-1,2,4-triazin-6-yl)benzonitrile(4.0 g, 11.3 mmol), K₂CO₃ (6.2 g, 21.2 mmol), and DMSO (113 mL) werecombined in a round bottom flask and cooled to 0° C. H₂O₂ (38 mL of 35%solution) was then added dropwise and the reaction was warmed to rt andstirred for 1 h. The reaction mixture was diluted with EtOAc and washedwith satd. aq. NaHCO₃ and brine. The organic layer was dried over sodiumsulfate, filtered, concentrated, and purified using silica gelchromatography to afford a white solid (3.3 g), m/z=371.1 [M+H].

EXAMPLE 16 Preparation of (1-(6-Methoxypyridin-2-yl)cyclobutyl)methanamine

1-(6-Fluoropyridin-2-yl)cyclobutanecarbonitrile

To a 0° C. solution of 2,6-difluoropyridine (5.0 g, 43 mmol),cyclobutanecarbonitrile (3.5 g, 43 mmol), and toluene (100 mL) was addedsodium hexamethyldisilazide (NaHMDS, 2.0 M in THF, 24 mL, 47 mmol). Theresulting mixture was warmed to rt and stirred for 2 h. The mixture wasthen diluted with EtOAc (200 mL) and water (100 mL). The aqueous layerwas extracted with EtOAc and the combined organic phases were washedwith brine, dried over Na₂SO₄, concentrated, and purified using silicagel chromatography to provide the desired product (4.9 g) as a colorlessoil.

1-(6-Methoxypyridin-2-yl)cyclobutanecarbonitrile

To anhydrous methanol (6 mL) at 0° C. under nitrogen was added sodiummetal (ca 1 g) and the mixture stirred for 30 min.1-(6-fluoropyridin-2-yl)cyclobutanecarbonitrile (1.6 g, 9.1 mmol) wasthen added, and the resulting mixture heated to 75° C. for 45 min. Thesolution was cooled to room temperature and partitioned between waterand EtOAc. The layers were separated, the aqueous phase was extractedwith EtOAc, and the combined organic phases were washed with brine,dried over Na₂SO₄, and concentrated in vacuo to give the desired product(1.7 g) as an oil.

(1-(6-Methoxypyridin-2-yl)cyclobutyl)methanamine

To a stirred solution of1-(6-methoxypyridin-2-yl)cyclobutanecarbonitrile (1.7 g, 8.8 mmol) inTHF (20 mL) was added lithium aluminum hydride solution (1.0 M in THF,11 mL, 11 mmol). The mixture was refluxed for 1.5 h and allowed to coolto room temperature. Water (0.43 mL) was slowly added, followed by 0.43mL of 3 M NaOH, and then three additions of 0.43 mL of water. Theresulting mixture was filtered through diatomaceous earth and rinsedwith THF. The combined organics were dried over Na₂SO₄ and concentratedto dryness to give the desired product (1.6 g) as a viscous oil.

EXAMPLE 17 Preparation of 1-(3-Fluoropyridin-2-yl)cyclobutanamineExample 5(a)

1-(3-Fluoropyridin-2-yl)cyclobutanecarboxamide

To a 250 mL round bottom flask was added DMSO (60 mL) and1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (2.96 g, 16.8 mmol), andthe mixture was stirred until homogenous. Potassium carbonate (7.0 g,50.4 mmol) was then added and the reaction mixture was cooled to 0° C.,followed by the addition of 35% hydrogen peroxide (6.5 mL). The reactionwas stirred at 0° C. for 30 min and then warmed to rt. At this time, thereaction was diluted with water (50 mL) and ethyl acetate (100 mL).After transferring to a separatory funnel and shaking, the organic layerwas separated from the aqueous layer and then washed with brine (3×50mL). The organic layer was then dried over Na₂SO₄, filtered, andconcentrated to give a crude solid that was purified by silica gelchromatography (10% EtOAC/hexanes) to afford 1.92 g of1-(3-fluoropyridin-2-yl)cyclobutanecarboxamide as a white solid.

Methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate

1-(3-fluoropyridin-2-yl)cyclobutanecarboxamide (1.92 g, 9.88 mmol) wasdissolved in methanol (20 mL) and potassium hydroxide (1.11 g, 19.8mmol, 2.0 equiv) was added. The mixture was sonicated until homogeneous,followed by the addition of iodosobenzene diacetate (4.77 g, 14.8 mmol).The reaction was stirred for 20 min and then diluted with water (100 mL)and ethyl acetate (125 mL). After transferring to a separatory funneland shaking, the organic layer was separated from the aqueous layer, andthe aqueous layer was extracted with EtOAc (50 mL). The combined organiclayers were then dried over Na₂SO₄, filtered, and concentrated to give acrude oil that was purified by silica gel chromatography (40%EtOAC/hexanes) to afford 1.47 g of methyl1-(3-fluoropyridin-2-yl)cyclobutylcarbamate as a white solid.

1-(3-Fluoropyridin-2-yl)cyclobutanamine

To a 20 mL microwave reaction vial was added methyl1-(3-fluoropyridin-2-yl)cyclobutylcarbamate (1.47 g, 6.56 mmol), ethanol(12 mL) and 3N aqueous sodium hydroxide (7 mL). The reaction mixture washeated in the microwave reactor at 150° C. for 30 min. The ethanol wasevaporated under reduced pressure and the mixture was extracted withethyl acetate (30 mL). The aqueous layer was then extracted with ethylacetate (2×30 mL). The organic layers were combined, dried over Na₂SO₄,filtered, and concentrated to give1-(3-fluoropyridin-2-yl)cyclobutanamine (1.01 g) as a crude yellow oilthat was used in the next reaction step without further purification.

EXAMPLE 18 Preparation oftrans-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine

1-(3-Fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile

To a solution of 3-methylenecyclobutanecarbonitrile (150 g, 1.61 mol, 1equiv) and 2-chloro-3-fluoropyridine (212 g, 1.61 mmol, 1 equiv) intoluene (1 L) was added NaHMDS (2 M in THF, 885 mL, 1.1 equiv) dropwiseat 0-10° C. Upon completion of addition, the reaction mixture was warmedto rt, stirred overnight, and quenched with NH₄Cl_((sat)) solution. Theorganic layer was washed with water (2×500 mL) and brine (500 mL), driedover Na₂SO₄, filtered, and concentrated to give the crude title compound(272 g) which was used in next step without further purification,m/z=189.1 [M+H].

1-(3-Fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile

To a mixture of1-(3-fluoropyridin-2-yl)-3-methylenecyclobutanecarbonitrile (272 g, 1.45mol) and RuCl₃.H₂O (9.0 g, 0.044 mol) in DCM (1 L), acetonitrile (1 L),and water (1.5 L) mixture was added solid NalO₄ (1235 g, 5.8 mol)portionwise at 10-30° C. Upon the completion of addition, the reactionwas stirred 1 h at 15° C. and overnight at rt. The solid precipitate wasfiltered off and washed with DCM (2×1000 mL). The organic layer waswashed with water (2×500 mL) and brine (500 mL), dried over Na₂SO₄, andconcentrated to provide a crude title compound as a dark solid (238 g),m/z=191.1 [M+H].

1-(3-Fluoropyridin-2-yl)-3-hydroxycyclobutanecarbonitrile

To a solution of 1-(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile(231 g, 1.22 mol) in a mixture of DCM (2 L) and MeOH (200 mL) was addedNaBH₄ portionwise at −78° C. The reaction mixture was stirred at −78° C.for 1 h and quenched with a mixture of methanol and water (1/1). Theorganic layer was washed with water (500 mL×3), dried over Na₂SO₄, andconcentrated. The residue was purified on silica gel (50% EtOAc/hexanes)to provide the title compound as an amber oil (185.8 g) m/z=193.2 [M+H].

trans-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile

To a solution of1-(3-fluoropyridin-2-yl)-3-hydroxycyclobutanecarbonitrile (185 g, 0.96mol) in DCM (1 L) was added DAST portionwise at 0-10° C. Upon thecompletion of addition, the reaction was refluxed for 6 h. The reactionwas cooled to rt and poured onto sat. NaHCO₃ solution. The mixture wasseparated and the organic layer was washed with water, dried overNa₂SO₄, and concentrated. The residue was purified on silica gel (100%DCM) to provide the title compound as a brown oil (116 g, 62%) in a 8:1trans:cis mixture. The above brown oil (107 g) was dissolved in toluene(110 mL) and hexanes (330 mL) at 70° C. The solution was cooled to 0° C.and stirred at 0° C. overnight. The precipitate was filtered and washedwith hexanes to provide the trans isomer as a white solid (87.3 g),m/z=195.1 [M+H].

trans-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine

A mixture oftrans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutanecarbonitrile (71 g,0.37 mol) and Raney nickel (˜7 g) in 7N ammonia in methanol (700 mL) wascharged with hydrogen (60 psi) for 2 days. The reaction was filteredthrough a celite pad and washed with methanol. The filtrate wasconcentrated under high vacuum to provide the title compound as a lightgreen oil (70 g), m/z=199.2 [M+H].

EXAMPLE 19 Preparation of4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-N-methylbenzamide

4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)benzoicacid

4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)benzonitrile(1.3 g, 74.5 mmol) was diluted in 20 mL of concentrated HCl and heatedin a microwave reactor at 110° C. for 30 min. The mixture was thenconcentrated and carried on to next step without further purification,(m/z [M−H]=414.1).

4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-N-methylbenzamide

4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)benzoicacid (0.5 g, 1.2 mmol) was diluted in 18 mL DMF and treated with HBTU(1.8 g, 4.8 mmol), HOBT (0.65 g, 4.8 mmol), methyl amine hydrochloride(0.32 g, 4.8 mmol), and DIEA (8.4 mL, 48 mmol). The mixture was stirredat 24° C. for 30 min, diluted with EtOAc, washed with water and brine,concentrated, and purified using reverse phase chromatography to afforda tan solid (0.25 g, (m/z [M−H]=429.3).

EXAMPLE 20 Preparation of1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutanecarbonitrile

To a 100 mL round bottom flask was added 2,3-dichloropyridine (2.9 g, 20mmol), 3,3-difluorocyclobutanecarbonitrile (2.1 g, 18 mmol), and toluene(50 mL). The mixture was cooled to ° C. and sodium hexamethyldisilazide(NaHMDS, 2.0 M in THF, 11 mL, 22 mmol) was added. The reaction mixturewas warmed to rt and stirred for 2 h. The mixture was then diluted withEtOAc (20 mL) and water (20 mL). The aqueous layer was extracted withEtOAc and the combined organic phases were washed with brine, dried overNa₂SO₄, and concentrated to provide the desired product (3.4 g) as acolorless oil.

EXAMPLE 21 Preparation of4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-hydroxybenzamide

4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzonitrile

6-(3-Bromo-6-fluoro-2-methoxyphenyl)-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-1,2,4-triazin-3-amine(448 mg, 0.93 mmol), zinc cyanide (131 mg, 1.1 mmol), Pd(PPh₃)₄ (296 mg,0.3 mmol), and DMF (5 mL) were combined and heated to 100° C. for 2 h.The reaction mixture was cooled and filtered through Celite. Thereaction mixture was then diluted with EtOAc and washed with satd. aq.NaHCO₃ and brine. The organic layer was dried over sodium sulfate,filtered, concentrated, and purified using silica gel chromatography toafford4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzonitrile(229 mg).

4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzamide

4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzonitrile(229 mg, 0.54 mmol), K₂CO₃ (200 mg, 1.4 mmol), and DMSO (5 mL) werecombined in a round bottom flask and cooled to 0° C. H₂O₂ (1 mL of 35%solution) was then added dropwise and the reaction was warmed to rt andstirred for 1 h. The reaction mixture was diluted with EtOAc and washedwith satd. aq. NaHCO₃ and brine. The organic layer was dried over sodiumsulfate, filtered, concentrated, and purified using silica gelchromatography to afford 210 mg of4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzamide.

4-Fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-hydroxybenzamide

Lithium iodide (1 g), pyridine (20 mL), and4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-methoxybenzamide(210 mg) were added to a round bottom flask. The reaction was heated to125° C. and stirred for 2 h. The reaction was concentrated, mixed withmethanol, filtered, and purified using reverse phase chromatography toafford 24 mg of4-fluoro-3-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)-2-hydroxybenzamide,m/z=430.1 [M+H].

EXAMPLE 22 Preparation ofN-((2-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methyl)acetamide

6-(5-((tert-Butyldimethylsilyloxy)methyl)thiazol-2-yl)-1,2,4-triazin-3-amine

Diisopropylamine (13.7 mL, 98 mmol) and THF (100 mL) were added to around bottom flask. The mixture was cooled to −78° C. and n-BuLi (2.5 M,40 mL, 100 mmol) was added. The reaction was stirred for 30 min,followed by the addition of(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl) (17.1 g, 75 mmol).The reaction was stirred to 30 min followed by the addition of zincbromide (18 g, 69 mmol). The reaction was stirred for 1 h at −78° C. andthen warmed to rt.

In a separate flask was added 6-bromo-1,2,4-triazin-3-amine (10.0 g,57.5 mmol), (PPh₃)₄Pd (12.1 g, 11.5 mmol), and THF (200 mL). The mixturewas heated to 80° C., followed by the dropwise addition (1 h) of(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)zinc(II) bromideprepared in the step above. The reaction was then cooled to rt, filteredthrough a silica pad, concentrated, and then purified using silica gelchromatography to afford 6.7 g the title compound as a light yellowsolid.

5-((tert-Butyldimethylsilyloxy)methyl)-2-(3-chloro-1,2,4-triazin-6-yl)thiazole

To a vial was added6-(5-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)-1,2,4-triazin-3-amine(2.5 g, 10.7 mmol), tetrabutylammonium chloride (6.3 g, 27.7 mmol) anddichloroethane (25 mL). The mixture was heated to 75° C., followed bythe addition of t-butyl nitrite (3.3 mL, 27.7 mmol). The reaction wasstirred at 75° C. for 3 h, followed by cooling to rt, quenching withbrine (200 mL). The reaction was extracted four times with CH₂Cl₂. Thecombined organic layers were dried over Na₂SO₄, concentrated, andpurified using silica gel chromatography to afford the 1.1 g of thetitle compound as an off-white solid.

(2-(3-(((trans)-3-Fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methanol

To a round bottom flask was added5-((tert-butyldimethylsilyloxy)methyl)-2-(3-chloro-1,2,4-triazin-6-yl)thiazole(1.1 g, 3.2 mmol),trans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (870 mg,4.3 mmol), potassium carbonate (1.3 g, 9.4 mmol), and CH₃CN (11 mL). Thereaction mixture was heated to 80° C. and stirred for 2 h. The reactionwas then diluted with EtOAc, filtered, and concentrated. The cruderesidue was suspended in methanol and concentrated HCl (1 mL) was added.The reaction was stirred for 30 min and then concentrated. The crude oilwas dissolved in ethyl acetate (50 mL) and washed twice with saturatedsodium carbonate (50 mL). The organic layers were dried over Na₂SO₄,concentrated, and purified using silica gel chromatography to afford 470mg of the title compound as an off-white solid.

6-(5-(Aminomethyl)thiazol-2-yl)-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-1,2,4-triazin-3-amine

To a vial containing(2-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methanol(457 mg, 1.17 mmol) was added triphenylphosphine (460 mg, 1.75 mmol),phthalimide (257 mg, 1.75 mmol), DIPEA (1 mL), and THF (10 mL).Diisopropylazodicarboxylate (350 mg, 1.75 mmol) was then added, and thereaction was stirred for 30 min. The reaction was quenched withsaturated sodium bicarbonate solution (10 mL) and extracted three timeswith ethyl acetate (50 mL). The organic layers were dried over Na₂SO₄,concentrated, and purified using silica gel chromatography to afford 670mg of2-((2-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methyl)isoindoline-1,3-dioneas an off-white solid. This solid was dissolved in methanol (10 mL) andhydrazine (1 mL). The reaction was stirred for 12 h, concentrated, andthen purified using reverse phase chromatography to afford 250 mg of6-(5-(aminomethyl)thiazol-2-yl)-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-1,2,4-triazin-3-amine.

N-((2-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methyl)acetamide

To a stirring solution of6-(5-(aminomethyl)thiazol-2-yl)-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-1,2,4-triazin-3-amine(250 mg, 643 μmol) in CH₂Cl₂ (10 mL) was added acetic anhydride (324 mg,3.2 μmol). The reaction was stirred for 30 min, followed by quenchedwith saturated sodium bicarbonate solution (10 mL) and extracted threetimes with CH₂Cl₂ (50 mL). The organic layers were dried over Na₂SO₄,concentrated, and purified using reverse phase chromatography to afford224 mg ofN-((2-(3-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)-1,2,4-triazin-6-yl)thiazol-5-yl)methyl)acetamideas a white solid, m/z=432.1 [M+H].

EXAMPLE 23 Preparation of2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carboxamide

6-(5-Bromothiazol-2-yl)-1,2,4-triazin-3-amine. To a vial was added6-(thiazol-2-yl)-1,2,4-triazin-3-amine (600 mg, 3.4 mmol), methanol (1.2mL), water (0.6 mL). The mixture was cooled to 0° C. and bromine (816mg, 5.1 mmol) was added. The reaction was stirred for 45 min and thenquenched with saturated sodium bicarbonate solution (20 mL) andextracted three times with ethyl acetate (50 mL). The organic layerswere dried over Na₂SO₄, concentrated, and purified using silica gelchromatography to afford 320 mg of6-(5-bromothiazol-2-yl)-1,2,4-triazin-3-amine as an off-white solid.

2-(3-Amino-1,2,4-triazin-6-yl)thiazole-5-carbonitrile

6-(5-Bromothiazol-2-yl)-1,2,4-triazin-3-amine (300 mg, 1.15 mmol), zinccyanide (340 mg, 2.30 mmol), Pd(PPh₃)₄ (133 mg, 0.13 mmol), and DMF (5mL) were combined and heated to 160° C. for 12 h. The reaction mixturewas cooled, diluted with CH₂Cl₂ (30 mL), filtered through silica gel,eluted with EtOAc, and concentrated. The crude product was then purifiedusing silica gel chromatography to afford 30 mg of2-(3-amino-1,2,4-triazin-6-yl)thiazole-5-carbonitrile.

2-(3-Bromo-1,2,4-triazin-6-yl)thiazole-5-carbonitrile

2-(3-Amino-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (30 mg, 0.15 mmol)was dissolved in 1 mL of bromoform and heated to 90° C. Isoamyl nitrite(88 mg, 0.75 mmol) was added and stirred at 90° C. for 2 h. The reactionmixture was then concentrated and used directly in the next reaction.

2-(3-(2-(3-(Difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile

To a scintillation vial was added2-(3-bromo-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (directly fromabove reaction), 2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-amine (100mg, 500 μmol), and CH₃CN (2 mL). The reaction was heated to 90° C. andstirred for 12 h. The reaction was then concentrated and purified usingsilica gel chromatography to afford 15 mg of2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile.

2-(3-(2-(3-(Difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carboxamide

2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile(15 mg, 38 μmol), K₂CO₃ (50 mg, 0.35 mmol), and DMSO (1 mL) werecombined in a vial and cooled to 0° C. H₂O₂ (0.1 mL of 35% solution) wasthen added and the reaction was warmed to rt and stirred for 1 h. Aceticacid (0.1 mL) was added, and the reaction was filtered and then purifiedusing reverse phase chromatography to afford 23 mg of2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carboxamideas a white solid, m/z=408.3 [M+H].

EXAMPLE 24 Preparation of3-(5-Fluoro-6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridin-3-yl)benzamide

5-Bromo-3-fluoro-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridin-2-amine

To a microwave tube was added 5-bromo-2-chloro-3-fluoropyridine (1.5 g,7.4 mmol),((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (2.2 g,11.1 mmol), and DIPEA (4.9 mL, 29.7 mmol). The tube was sealed, heatedat 110° C., and stirred for 12 h. The reaction was then directlypurified using silica gel chromatography to afford 2.5 g of5-bromo-3-fluoro-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridin-2-amineas a white solid.

3-(5-Fluoro-6-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridin-3-yl)benzamide

5-Bromo-3-fluoro-N-(((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridin-2-amine(1.0 g, 2.6 mmol), 3-carbamoylphenylboronic acid (0.54 g, 3.2 mmol),potassium carbonate (1.5 g, 10.8 mmol), and methanol (25 mL) was addedto a 100 mL round bottom flask and then degassed with nitrogen for 5min. Silica-supported 1,1′-Bis(diphenylphosphino)ferrocene (1.0 g, 0.28mmol/g) was added, and the reaction was refluxed in methanol for 2 h.The reaction mixture was then filtered, concentrated, and purified usingsilica gel chromatography to afford 2.0 g of the title compound as asolid, m/z=413.3 [M+H]

EXAMPLE 25 Preparation and Assay of Fast Skeletal Myofibrils

Preparation of fast skeletal myofibrils. Rabbit skeletal myofibrils wereprepared based upon the method of Herrmann et al. (Biochem.32(28):7255-7263(1993). Myofibrils were prepared from rabbit psoasmuscle purchased from Pel-Freez Biologicals (Arkansas) within 2 days ofordering, stored on ice. Minced muscle was homogenized in 10 volumes ofice-cold “standard” buffer (50 mM Tris, pH 7.4, 0.1 M potassium acetate,5 mM KCl, 2 mM DTT, 0.2 mM PMSF, 10 μM leupeptin, 5 μM pepstatin, and0.5 mM sodium azide) containing 5 mM EDTA and 0.5% Triton X-100 using anOmni-Macro homogenizer. Myofibrils were recovered by low speedcentrifugation (3000 rpm for 10 minutes) and washed 2 times in theTriton X-100 containing buffer to ensure removal of cellular membrane.Following the Triton washes, myofibrils were washed 3 times in“standard” buffer containing 2 mM magnesium acetate. A final wash inassay buffer (12 mM PIPES, pH 6.8, 60 mM KCl, 1 mM DTT) was performedand brought to 10% sucrose for flash freezing in liquid nitrogen andstorage at −80° C.

Activation of Fast Skeletal Myofibrils.

Fast fiber activators were identified by measuring the enzymaticactivity of muscle myofibril preparations using the proprietary PUMA™(see, e.g., U.S. Pat. Nos. 6,410,254, 6,743,599, 7,202,051, and7,378,254) assay system. Myofibril preparations consisted of rabbitskeletal muscle (approximately 90% fast fibers) that had beenmechanically homogenized and washed with a detergent (triton X-100) toremove cellular membranes. This preparation retained all of thesarcomeric components in a native conformation and the enzymaticactivity was still regulated by calcium. Compounds were tested using amyofibril suspension and a level of calcium sufficient to increaseenzymatic activity of the myofibrils to 25% of their maximal rate(termed pCa25). Enzymatic activity was tracked via a pyruvate kinase andlactate dehydrogenase-coupled enzyme system. This assay regeneratesmyosin-produced ADP into ATP by oxidizing NADH, producing an absorbancechange at 340 nm. The buffering system was 12 mM Pipes, 2 mM MgCl₂, 1 mMDTT at pH 6.8 (PM12 buffer). Data was reported as AC1.4, which is theconcentration at which the compound increased the enzymatic activity by40%. The results are summarized in Table 2 below.

EXAMPLE 26 Preparation and Assay of Sarcomeric Proteins from SkeletalMuscle

Powder Preparation

1. Volumes are given per about 1000 g of the minced muscle.2. Pre-cut and boil cheesecloth for 10 min in water. Drain and dry.3. Mince chicken breast in a prechilled meat grinder.4. Extract with stirring in 2 L of 0.1 M KCl, 0.15 M K-phosphate, pH 6.5for 10 min at 4° C. Spin 5000 rpm, 10 min, 4° C. in JLA. Collect thepellet.5. Extract pellets with stirring with 2 L of 0.05 M NaHCO₃ for 5 min.Spin 5000 rpm, 10 min, 4° C. in JLA. Collect the pellet. Repeat theextraction once more.6. Extract the filtered residue with 2 L of 1 mM EDTA, pH 7.0 for 10 minwith stirring.7. Extract with 2 L of H₂O for 5 min with stirring. Spin 10000 rpm, 15min, 4° C. in JLA. Carefully collect the pellet, part of which will beloose and gelatinous.8. Extract 5 times with acetone (2 L of acetone for 10 min each withstirring). Squeeze through cheesecloth gently. All acetone extractionsare performed at room temperature. Acetone should be prechilled to 4° C.9. Drying: Place the filtered residue spread on a cheesecloth in a largeglass tray and leave in a hood overnight. When the residue is dry, putin a wide mouth plastic bottle and store at 20° C.

Alternate Powder Preparation

(See Zot & Potter (1981) Prep. Biochem. 11(4) pp. 381-395)1. Dissect left ventricles of the cardiac muscle. Remove as much of thepericardial tissue and fat as possible. Grind in a prechilled meatgrinder.

Weigh.

2. Prepare 5 volumes of Extract buffer (see below). Homogenize the meatin a blender, 4 times 15 sec on blend with 15 secs in between. Do thiswith 1 volume (weight/volume) of buffer taken from the 5 volumes alreadyprepared. Add the homogenate back to the extract buffer and stir untilwell mixed (5 minutes).3. Filter through one layer of cheesecloth in large polypropylenestrainer. Resuspend back into 5 volumes of extract buffer as above.4. Repeat Step 3 four more times. At the end, do not resuspend inextraction buffer but proceed to Step 5. The pellets should be yellowwhite.5. Resuspend in 3 volumes (according to original weight) of 95% coldethanol. Stir for 5 min and squeeze through cheesecloth as above, repeattwo more times.6. Weigh squeezed residue and then resuspend in 3 volumes (newweight/volume) of cold diethyl ether.7. Repeat Step 6 a total of three times.8. Leave overnight in a single layer on a cheesecloth in a glass tray.9. When dry, collect the powder, weigh and store in a wide-mouth jar at4° C.

EXTRACT BUFFER: 50 mM KCl, 5 mM Tris pH 8.0 Prepare as 50 timesconcentrate. For 2 L: 250 mM Tris pH 8.0. Tris Base (121.14 g/mol, 60.6g), pH to 8.0 with conc. HCl, then add 2.5 M KCl (74.55 g/mol, 372 g).

Actin Preparation

1. Extract powder (as described above) with 20 ml buffer A (see below,add BME and ATP just prior to use in each of the following steps) pergram of powder (200 ml per 10 g). Use a large 4 L beaker for 150 g ofpowder. Mix vigorously to dissolve powder. Stir at 4° C. for 30 min.2. Separate extract from the hydrated powder by squeezing throughseveral layers of cheesecloth. Cheesecloth should be pre-sterilized bymicrowaving damp for 1-2 min.3. Re-extract the residue with the same volume of buffer A and combineextracts.4. Spin in JLA10 rotor(s) for 1 hr at 10K rpm (4° C.). Collectsupernatant through 2 layers of cheesecloth.5. Add ATP to 0.2 mM and MgCl₂ to 50 mM. Stir on stir plate at 4° C. for60 minutes to allow actin to polymerize/form para-crystals.6. Slowly add solid KCl to 0.6 M (45 g/l). Stir at 4° C. for 30 min.7. Spin in JLA10 rotor(s) at 10K rpm for 1 hr.8. Depolymerization: Quickly rinse surface of pellets with buffer A anddispose of wash. Soften the pellets by pre-incubation on ice with smallamount of buffer A in each tube (use less than half of finalresuspension volume total in all tubes). Resuspend by hand first withcell scraper and combine pellets. Wash tubes with extra buffer using a25 ml pipette and motorized pipettor, aggressively removing actin fromsides of tubes. Homogenize in large dounce in cold buffer A on ice. Use3 ml per gram of powder originally extracted.9. Dialyze against buffer A with 4 changes over 48 hour period.10. Collect dialyzed actin and spin in the 45Ti rotor at 40K rpm for 1.5hr (4° C.).11. Collect supernatant (G-Actin). Save a sample for gel analysis anddetermination of protein concentration.12. To polymerize G-actin for storage, add KCl to 50 mM (from 3 Mstock), MgCl₂ to 1 mM, and NaN₃ to 0.02% (from 10% stock). Store at 4°C. Do not freeze.Buffer A: 2 mM tris/HCl, 0.2 mM CaCl₂, 0.5 mM (36 μl/L)2-mercaptoethanol, 0.2 mM Na₂ ATP (added fresh), and 0.005% Na-azide; pH8.0.

Purification of Skeletal Muscle Myosin

(See Margossian, S. S. and Lowey, S. (1982) Methods Enzymol. 85, 55-123;and Goldmann, W. H. and Geeves, M. A. (1991) Anal. Biochem. 192, 55-58)Solution A: 0.3 M KCl, 0.15 M potassium phosphate, 0.02 M EDTA, 0.005 MMgCl₂, 0.001 M ATP, pH 6.5.Solution B: 1 M KCl, 0.025 M EDTA, 0.06 M potassium phosphate, pH 6.5.Solution C: 0.6 M KCl, 0.025 M potassium phosphate, pH 6.5.Solution D: 0.6 M KCl, 0.05 M potassium phosphate, pH 6.5.Solution E: 0.15 M potassium phosphate, 0.01 M EDTA, pH 7.5.Solution F: 0.04 M KCl, 0.01 M potassium phosphate, 0.001 M DTT, pH 6.5.Solution G: 3 M KCl, 0.01 M potassium phosphate, pH 6.5.All procedures are carried out at 4° C.1. Obtain approx. 1000 g skeletal muscle, such as rabbit skeletalmuscle.2. Grind twice; extract with 2 L solution A for 15 min while stirring;add 4 L cold H₂O, filter through gauze; dilute with cold H₂O to ionicstrength of 0.04, (about 10-fold); let settle for 3 h; collectprecipitate at 7,000 rpm in GSA rotor for 15 min.3. Disperse pellet in 220 ml solution B; dialyze overnight against 6 Lsolution C; slowly add 400 ml equal volume cold distilled H₂O; stir for30 min; centrifuge at 10,000 rpm for 10 min in GSA rotor.4. Centrifuge supernatant at 19,000 rpm for 1 h.5. Dilute supernatant to ionic strength of 0.04 (˜8-fold); let myosinsettle overnight; collect about 5-6 L fluffy myosin precipitate bycentrifuging at 10,000 rpm for 10 min in GSA rotor.6. Resuspend pellet in minimal volume of solution G; dialyze overnightagainst 2 L solution D; centrifuge at 19,000 rpm for 2 h, in cellulosenitrate tubes; puncture tubes and separate myosin from fat and insolublepellet.7. Dilute supernatant to 5-10 mg/ml and dialyze against solution Eextensively, load onto DEAE-sephadex column.8. Pre-equilibrate with solution E; apply 500-600 g myosin at 30 ml/h;wash with 350 ml solution E; elute with linear gradient of 0-0.5 M KClin solution E (2×1 liter); collect 10 ml fractions; pool myosinfractions (>0.1 M KCl); concentrate by overnight dialysis againstsolution F; centrifuge at 25,000 rpm for 30 min; store as above.9. The myosin is then cut with chymotrypsin or papain in the presence ofEDTA to generate the S1 fragment which is soluble at the low saltconditions optimal for ATPase activity (Margossian, supra).

Preparation and Assay

Myosin is prepared by precipitation from salt extracts of rabbit psoasmuscle, and a soluble S1 fraction is prepared by digestion withchymotrypsin (Margossian and Lowey, 1982).

Actin is purified by first preparing an ether powder of cardiac muscle(Zot HG and Potter J D. (1981) Preparative Biochemistry 11:381-395) asdescribed above. Subsequently, actin is cycled between the filamentousand soluble state through rounds of centrifugation and dialysis (SpudichJ A and Watt S. (1971) J. Biol. Chem. 246:4866-4871).

Tropomyosin is extracted from the ether powder and separated from theother proteins based on pH dependent precipitations followed bysuccessive ammonium sulfate cuts at 53% and 65% (Smillie L B. (1981)Methods Enzymol 85 Pt B:234-41). The troponins are isolated as an intactcomplex of TnC, TnT, and TnI. Ether powder is extracted in a high saltbuffer. Successive ammonium sulfate cuts of 30% and 45% are done; theprecipitate is solubilized by dialysis into a low salt buffer and thenfurther purified on a DEAE Toyopearl column with a 25-350 mM KClgradient. There is no measurable ATPase in any of the components exceptfor myosin which naturally had a very low basal ATPase in the absence ofactin.

Prior to screening, the actin, tropomyosin, and troponin complex aremixed together in the desired ratio (e.g., 7:1:1) to achieve maximalcalcium regulation of the actin filament. The screen is conducted at aconcentration that gives 25% activation. This calcium concentration isin the physiological range during muscle contraction.

To measure the generation of ADP during the reaction, a pyruvatekinase/lactate dehydrogenase/NADH coupled enzyme system (PK/LDH) isadded to the actin. The myosin is kept separately, and added to theregulated thin filaments to initiate the reaction. Oxidation of NADH ismonitored in real time, so that kinetic curves are obtained. Compoundsare dissolved in DMSO and spotted onto the bottoms of 384 well plates at10 to 40 μg/ml final concentration.

Using procedures similar to those described herein, utilizing reagentsand intermediates commercially available (e.g., Sigma-Aldrich,) orreadily synthesized by one of skill in the art, the compounds in Table 2were synthesized, characterized and tested. AC1.4 values were determinedaccording to the procedure described in Example 25, and the reportedmedian AC1.4 values are as follows: A=<1 uM; B=1-10 uM; C=10-20 uM;D=>20 uM.

TABLE 2 m/z Mean Compound Structure (M + H) AC1.4(6-bromo(2-pyridyl))[2-(4-fluorophenyl)-2- methylpropyl]amine

323.0 C [2-(4-fluorophenyl)-2-methylpropyl][6-(2-methylprop-1-enyl)(2-pyridyl)]amine

299.4 D [6-(4-fluorophenyl)(2-pyridyl)][2-(4-fluorophenyl)-2-methylpropyl]amine

339.1 D [4-(4-fluorophenyl)(2-pyridyl)][2-(4-fluorophenyl)-2-methylpropyl]amine

339.1 D 4-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)benzamide

364.0 B 3-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)benzamide

364.0 A 6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridine-3-carbonitrile

270.1 C 3-(6-{[2-(4-fluorophenyl)ethyl]amino}-3- pyridyl)benzamide

336.1 D 6-{[2-(4-f1uorophenyl)-2- methylpropyl]amino}pyridine-3-carboxamide

288.1 C N-[(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}(3-pyridyl))methyl]methoxycarboxamide

332.0 D tert-butyl 2-[(5-bromo-2- pyridyl)amino]acetate

288.0 D 3-{6-[2-(4-fluorophenyl)acetylamino]-3- pyridyl}benzamide

350.1 D 1-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)ethane-1,2- diol

305.0 D 3-(6-{[(2S)-2-(4- fluorophenyl)propyl]amino}-3-pyridyl)benzamide

350.0 B 3-(6-{[(2R)-2-(4- fluorophenyl)propyl]amino}-3-pyridyl)benzamide

350.0 B 3-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)propane- 1,2-diol

319.0 D N-[2-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}(3-pyridyl))ethyl]methoxycarboxamide

346.0 D [2-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}(3-pyridyl))ethyl](methylsulfonyl)amine

366.0 D N-[2-(6-{[2-(4-fluorophenyl)-2- methylpropyl]amino}-3-pyridyl)ethyl]acetamide

330.0 D 2-{[2-(4-fluorophenyl)-2- methylpropyl]amino}quinoline-6-carboxamide

338.1 B (4-phenyl(2- pyridyl))(phenylcyclobutyl)amine

301.2 C (6-phenyl(2- pyridyl))(phenylcyclobutyl)amine

301.2 D (5-phenyl(2- pyridyl))(phenylcyclobutyl)amine

301.2 B 3-[5-fluoro-6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)-3- pyridyl]benzamide

413.3 B 3-(3-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-1,2,4-triazin-6- yl)benzamide

366.1 B [6-(3-amino(1H-indazol-5-yl))(1,2,4-triazin-3-yl)][2-(4-fluorophenyl)-2- methylpropyl]amine

378.1 A 3-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-1,2,4-triazin-3- yl)benzamide

366.1 B 3-[6-({[(4- fluorophenyl)cyclobutyl]methyl}amino1,2,4-triazin-3-yl]benzamide

378.1 A 2-fluoro-5-(3-{[2-(4-fluorophenyl)-2-methylpropyl]amino}(1,2,4-triazin-6- yl))benzamide

369.1 D 2-fluoro-5-[3-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)(1,2,4-triazin-6-yl)]benzenecarbonitrile

379.1 C (6-(1H-indazol-5-yl)(1,2,4-triazin-3-yl)){[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

376.1 B [6-(3-amino(1H-indazol-5-yl))(1,2,4-triazin-3-yl)]{[(3-fluoro(2- pyridyl))cyclobutyl]methyl}amine

391.1 B (6-(1H-indazol-5-yl)(1,2,4-triazin-3-yl))[2-(3-fluoro(2-pyridyl))-2-methylpropyl]amine

364.2 C 4-fluoro-3-(3-{[(3-fluoro(2-pyridyl))cyclobutyl]amino}(1,2,4-triazin-6- yl))benzamide

383.2 B 3-{3-[(tert-butyl)amino](1,2(4-triazin-6-yl)}- 4-fluorobenzamide

290.1 D 4-fluoro-3-(3-{[(4- fluorophenyl)cyclobutyl]amino}(1,2,4-triazin-6-yl))benzamide

382.1 B 4-fluoro-3-(3-{[1-(4-fluorophenyl)-isopropyl]amino}(1,2,4-triazin-6- yl))benzamide

370.2 A 3-[3-({[6-(difluoromethoxy)(2-pyridyl)]cyclobulyl}amino)(1,2,4-triazin-6- yl)]-4-fluorobenzamide

431.1 A [6-(4-bromophenyl)(1,2,4-triazin-3-yl)]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

415.1 C 3-[3-({1-[6-(difluoromethoxy)(2-pyridyl)]-isopropyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzamide

419.1 A [6-(4-aminophenyl)(1,2,4-triazin-3-yl)]{[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

350.1 B {[6-(difluoromethoxy)(2- pyridyl)]cyclobutyl}[6-(5-bromo-2-fluorophenyl)(1,2,4-triazin-3-yl)]amine

467.1 B 4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzamide

371.1 B 4-fluoro-3-(3-{[(3-fluoro(2-pyridyl))ethyl]amino}(1,2,4-triazin-6- yl))benzamide

357.1 C 3-[3-({[6-(difluoromethoxy)(2-pyridyl)]methyl}amino)(1,2,4-triazin-6-yl)]- 4-fluorobenzamide

391.1 D 3-[3-({[6-(difluoromethoxy)(2-pyridyl)]ethyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzamide

405.1 C 1-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}-1,2,4-triazin-6- yl)pyrazole-4-carboxamide

343.1 D 1-(3-{[(3-fluoro-2- pyridyl)cyclobutyl]amino}-1,2,4-triazin-6-yl)pyrazole-4-carboxamide

355.1 D 1-(3-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-1,2,4-triazin-6- yl)pyrazole-4-carboxamide

356.1 B 1-[3-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)-1,2,4-triazin-6-yl]pyrazole-4-carboxamide

369.1 B 1-[3-({1-[6-(difluoromethoxy)(2-pyridyl)]-isopropyl}amino)-1,2,4-triazin-6- yl]pyrazole-4-carboxamide

391.3 B 2-[3-({1-[6-(difluoromethoxy)(2-pyridyl)]-isopropyl}amino)-1,2,4-triazin-6-yl]-1,3- thiazole-5-carboxamide

408.3 B 3-(3-{[(2-pyridylcyclobutyl)methyl]amino}-1,2,4-triazin-6-yl)benzenecarbonitrile

343.2 B 3-(3-{[(2-pyridylcyclobutyl)methyl]amino}-1,2,4-triazin-6-yl)benzamide

361.2 B 3-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}-1,2,4-triazin-6- yl)benzamide

353.1 B 4-fluoro-3-(3-{[1-methyl-1-(6-methyl(2-pyridyl))ethyl]amino}(1,2,4-triazin-6- yl))benzamide

367.1 C 3-(3-{[1-(3-chloro(2-pyridyl))-isopropyl]amino}-1,2,4-triazin-6- yl)benzamide

369.1 B 3-(3-{[1-(3-chloro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6-yl))-4- fluorobenzamide

387.1 B 4-fluoro-3-(3-{[1-(5-fluoro-6-methyl(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzamide

385.1 B 4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzoic acid

372.2 C [6-(3-amino-6-fluorophenyl)(1,2,4-triazin-3-yl)][1-(3-fluoro(2-pyridyl))- isopropyl]amine

343.2 B [4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))phenyl](methylsulfonyl)amine

421.1 C 5-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}-1,2,4-triazin-6-yl)-1H-2- hydroindazol-3-one

366.1 B 2-fluoro-5-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzoic acid

372.1 D 2-fluoro-5-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzamide

371.2 D N-((2S)-2,3-dihydroxypropyl)[4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))- isopropyl]amino}(1,2,4-triazin-6-yl))phenyl]carboxamide

445.3 C N-[4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]methoxycarboxamide

401.1 B amino[4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]sulfonamide

422.1 B 3-[3-({1-[6-(difluoromethyl)(2-pyridyl)]-isopropyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzamide

403.1 B 3-[3-({1-[6-(difluoromethyl)(2-pyridyl)]-isopropyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzenecarbonilrile

385.1 B 2-[3-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}-1,2,4-triazin-6- yl)phenyl]acetamide

367.1 D methyl 3-fluoro-4-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzoate

386.2 D 3-fluoro-4-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzamide

371.2 D 3-fluoro-4-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzoic acid

372.2 D [4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]methan-1-ol

358.3 C {6-[5-(aminomethyl-2-fluorophenyl](1,2,4-triazin-3-yl)}[1-(3-fluoro(2-pyridyl))- isopropyl]amine

357.3 D N-{[4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]methyl}acetamide

399.3 D 4-fluoro-3-(3-{[1-(3-fluoro-6-methyl(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))benzamide

385.1 B 2-amino-N-{[4-fluoro-3-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}(1,2,4-triazin-6- yl))phenyl]methyl}acetamide

414.2 B [1-(3-fluoro(2-pyridyl))-isopropyl](6-(1,3-thiazol-2-yl)(1,2,4-triazin-3-yl))amine

317.1 D 4-fluoro-3-[3-({1-methyl-1-[3-(methylsulfonyl)phenyl]ethyl}amino)(1,2,4- triazin-6-yl)]benzamide

430.2 D methyl 4-fluoro-3-[3-({1-methyl-1-[3-(methylsulfonyl)phenyl]ethyl}amino)(1,2,4- triazin-6-yl)]benzoate

445.2 D [2-(3-{[1-(3-chloro(2-pyridyl))-isopropyl]amino}-1,2,4-triazin-6-yl)-1,3- thiazol-5-yl]methan-1-ol

363.0 D 2-[2-(3-{[1-(3-fluoro(2-pyridyl))-isopropyl]amino}-1,2,4-triazin-6-yl)-1,3- thiazol-5-yl]acetamide

374.3 D 3-[3-({1-[3-(difluoromethyl)(2-pyridyl)]-isopropyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzenecarbonitrile

385.1 D 3-[3-({1-[3-(difluoromethyl)(2-pyridyl)]-isopropyl}amino)(1,2,4-triazin-6-yl)]-4- fluorobenzamide

403.1 C {6-[5-(aminomethyl)(1,3-thiazol-2-yl)](1,2,4-triazin-3-yl)}[1-(3-chloro(2- pyridyl))-isopropyl]amine

362.3 D N-{[2-(3-{[1-(3-chloro(2-pyridyl))-isopropyl]amino}-1,2,4-triazin-6-yl)-1,3- thiazol-5-yl]methyl}acetamide

404.3 D 1-(3-{[1-(3-chloro(2-pyridyl))-isopropyl]amino}-1,2,4-triazin-6- yl)pyrazole-4-carboxamide

359.3 D {2-[3-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)-1,2,4-triazin-6-yl]-1,3-thiazol-5-yl}methan-1-ol

391.3 B 3-[3-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]benzamide

397.2 A {6-[5-(aminomethyl)(1,3-thiazol-2-yl)](1,2,4-triazin-3-yl)}{[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amine

390.3 B N-({2-[3-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]-1,3-thiazol-5-yl}methyl)acetamide

432.1 B methyl 3-(3-{[2-(3-chloro(2-pyridyl))-2-methylpropyl]amino}(1,2,4-triazin-6-yl))-4- fluorobenzoate

416.2 D methyl 3-[3-({[(3-chloro(2-pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorobenzoate

428.2 B methyl 4-fluoro-3-(3-{[(2-pyridylcyclobutyl)methyl]amino}(1,2,4- triazin-6-yl))benzoate

394.3 C 3-[3-({[(3-chloro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4-triazin-6-yl)]-4-fluorobenzamide

413.2 A 3-(3-{[2-(3-chloro(2-pyridyl))-2-methylpropyl]amino}(1,2,4-triazin-6-yl))-4- fluorobenzamide

401.2 B 4-fluoro-3-(3-{[(2- pyridylcyclobutyl)methyl]amino}(1,2,4-triazin-6-yl))benzamide

379.3 B 3-[3-({[(3-chloro(2- pyridyl))cyclobutyl]methyl}amino)(1,2,4-triazin-6-yl)]-4-fluorobenzoic acid

414.2 A 3-(3-{[2-(3-chloro(2-pyridyl))-2-methylpropyl]amino}(1,2,4-triazin-6-yl))-4- fluorobenzoic acid

402.2 B 4-fluoro-3-[3-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]benzamide

415.1 A 3-[3-({[1-(3-chloro(2-pyridyl))-3-fluorocyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]benzamide

413.2 A 3-[3-({[1-(3-chloro(2-pyridyl))-3-fluorocyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorobenzamide

431.2 A 3-[3-({[1-(3-chloro(2-pyridyl))-3-fluorocyclobutyl]methyl}amino)-1,2,4- triazin-6-yl]benzenecarbonitrile

395.2 B 3-[3-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)-1,2,4-triazin-6-yl]benzamide

379.3 B 2-{2-[3-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)-1,2,4-triazin-6-yl]-1,3-thiazoI-5-yl}acetamide

418.2 C 2-{2-[3-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)-1,2,4-triazin-6-yl]-1,3-thiazol-5-yl}acetamide

400.3 C {2-[3-({[(3-fluoro-2- pyridyl)cyclobutyl]methyl}amino)-1,2,4-triazin-6-yl]-1,3-thiazol-5-yl}methan-1-ol

373.3 C 4-fluoro-3-[3-({[(3-fluoro(2-pyridyl))cyclobulyl]methyl}amino)(1,2,4- triazin-6-yl)]benzoic acid

398.1 B {4-fluoro-3-[3-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)(1,2,4-triazin-6-yl)]phenyl}-N-methylcarboxamide

411.1 B 4-fluoro-3-[3-({[(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]benzamide

397.1 A {3-[3-({[1-(3-chloro(2-pyridyl))-3-fluorocyclobutyl]methyl}amino)(1,2,4-triazin-6-yl)]phenyl}-N-methylcarboxamide

427.3 B {3-[3-({[1-(3-chloro(2-pyridyl))-3-fluorocyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorophenyl}-N-methylcarboxamide

445.2 A 3-[3-({[1-(3-chloro(2-pyridyl))-3,3-difluorocyclobutyl]methyl}amino)(1,2,4- triazin-6-yl)]-4-fluorobenzamide

449.2 A {3-[3-({[1-(3-chloro(2-pyridyl))-3,3-difluorocyclobulyl]methyl}amino)(1,2,4-triazin-6-yl)]-4-fluorophenyl}-N- methylcarboxamide

463.2 B {4-fluoro-3-[3-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)(1,2,4-triazin-6-yl)]phenyl}-N-methylcarboxamide

429.3 B {3-[3-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)(1,2,4-triazin-6-yl)]-4-hydroxyphenyl}-N- methylcarboxamide

427.2 A 3-[3-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobulyl]methyl}amino)(1,2,4-triazin-6-yl)]-4-hydroxybenzamide

413.2 A {3-[3-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobulyl]methyl}amino)(1,2,4-triazin-6-yl)]phenyl}-N-methylcarboxamide

411.3 B 4-fluoro3-[3-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)(1,2,4-triazin-6-yl)]-2-hydroxybenzamide

430.1 A

While the present invention has been described with reference to thespecific embodiments described herein, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, modifications may be made to adapt a particularsituation, material, composition of matter and/or process to theobjective, spirit and scope of the present invention. All suchmodifications are intended to be within the scope of the claims appendedhereto.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Z¹, Z³ and Z⁴are each CR¹ and Z² is N; or Z², Z³ and Z⁴ are each CR¹ and Z¹ is N; R¹,at each occurrence, is independently selected from the group consistingof hydrogen, halogen, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C(O)OR^(a),C(O)NR^(b)R^(c), OR^(a), NR^(b)R^(c), C₆₋₁₀ aryl and 5-10 memberedheteroaryl; R² is selected from the group consisting of C₃₋₈ cycloalkyl,C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl andNR^(b)R^(c), wherein each of the C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryland 5-10 membered heteroaryl groups is optionally substituted with 1, 2,3, 4 or 5 substituents selected from the group consisting of halogen,CN, oxo, (CH₂)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)NR^(b)R^(c), (CH₂)NR^(d)C(O)R^(a),(CH₂)NR^(d)C(O)OR^(a), (CH₂)NR^(d)C(O)NR^(b)R^(c),(CH₂)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)C₆₋₁₀ aryl and (CH₂)_(n)5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents; R⁴ is selected from the group consisting of hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c) andSO₂R^(a); R⁵ and R⁶ are each independently selected from the groupconsisting of hydrogen, halogen, C₁₋₆ alkyl and C₁₋₆ haloalkyl; oralternatively, R⁵ and R⁶ together with the carbon atom to which they arebound form a group selected from the group consisting of C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl and 3-8membered heterocycloalkenyl, each optionally substituted with 1, 2, 3, 4or 5 substituents selected from the group consisting of halogen, CN,oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl and C₁₋₆ haloalkyl; R⁷ is selected from the group consisting ofC₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,each optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfrom the group consisting of halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents; R⁸ and R⁹, at eachoccurrence, are each independently selected from the group consisting ofhydrogen, halogen and C₁₋₆ alkyl; X is selected from the groupconsisting of a bond, —(CH₂)_(p)—, —(CH₂)_(p)C(O)(CH₂)_(q)—,—(CH₂)_(p)O(CH₂)_(q)—, —(CH₂)_(p)S(CH₂)_(q)—,—(CH₂)_(p)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)C(O)O(CH₂)_(q)—,—(CH₂)_(p)OC(O)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)(CH₂)_(q)—,—(CH₂)_(p)C(O)NR^(d)(CH₂)_(q)—, —(CH₂)_(p)NR^(d)C(O)NR^(d)(CH₂)_(q)—,—(CH₂)_(p)NR^(d)SO₂(CH₂)_(q)—, and —(CH₂)_(p)SO₂NR^(d)(CH₂)_(q)—, R^(a),at each occurrence, is independently selected from the group consistingof hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents; R^(b) and R^(c), at each occurrence, are eachindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl, 5-10 membered heteroaryl,C(O)R^(g), C(O)OR^(g), C(O)NR^(i)R^(j) and SO₂R^(g), wherein each of theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents; R^(d), at each occurrence, is independently selected fromthe group consisting of hydrogen and C₁₋₆ alkyl; R^(e), at eachoccurrence, is independently selected from the group consisting ofhydrogen, CN, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl and C₁₋₆ haloalkyl; R^(f), ateach occurrence, is independently selected from the group consisting ofhalogen, CN, OR^(h), OC(O)R^(h), OC(O)OR^(h), OC(O)NR^(i)R^(j),NR^(i)R^(j), NR^(d)C(O)R^(h), NR^(d)C(O)OR^(h), NR^(d)C(O)NR^(i)R^(j),NR^(d)C(O)C(O)NR^(i)R^(j), NR^(d)C(S)R^(h), NR^(d)C(S)OR^(h),NR^(d)C(S)NR^(i)R^(j), NR^(d)C(NR^(e))NR^(i)R^(j), NR^(d)S(O)R^(h),NR^(d)SO₂R^(h), NR^(d)SO₂NR^(i)R^(j), C(O)R^(h), C(O)OR^(h),C(O)NR^(i)R^(j), C(S)R^(h), C(S)OR^(h), C(S)NR^(i)R^(j),C(NR^(e))NR^(i)R^(j), SR^(h), S(O)R^(h), SO₂R^(h), SO₂NR^(i)R^(j), C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(k)substituents; or two R^(f) substituents bound to a single carbon atom,together with the carbon atom to which they are both bound, form a groupselected from the group consisting of carbonyl, C₃₋₈ cycloalkyl and 3-8membered heterocycloalkyl; R^(g), at each occurrence, is independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl,phenyl, naphthyl, and C₇₋₁₁ aralkyl, each optionally substituted with 1,2, 3, 4 or 5 substituents selected from the group consisting of halogen,CN, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl and C₁₋₆ haloalkyl; R^(h), at eachoccurrence, is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(k)substituents; R^(i) and R^(j), at each occurrence, are eachindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl, 5-10 membered heteroaryl,C(O)R^(g), and C(O)OR^(g), wherein each of the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5substituents selected from the group consisting of halogen, CN, OH, C₁₋₆alkoxy, C₁₋₆ alkyl and C₁₋₆ haloalkyl; R^(k), at each occurrence, isindependently selected from the group consisting of halogen, CN, oxo,OH, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, NHC(O)C₁₋₆ alkyl,NHC(O)C₇₋₁₁ aralkyl, NHC(O)OC₁₋₆ alkyl, NHC(O)OC₇₋₁₁ aralkyl, C(O)C₁₋₆alkyl, C(O)C₇₋₁₁ aralkyl, C(O)OC₁₋₆ alkyl, C(O)OC₇₋₁₁ aralkyl, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein each C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₇₋₁₁ aralkyl substituent isoptionally substituted with 1, 2 or 3 substituents selected from thegroup consisting of OH, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆alkyl)₂, NHC(O)C₁₋₆ alkyl, NHC(O)C₇₋₁₁ aralkyl, NHC(O)OC₁₋₆ alkyl, andNHC(O)OC₇₋₁₁ aralkyl; m is 0, 1 or 2; n, at each occurrence,independently is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or
 2. 2. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein m is
 0. 3. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein m is
 1. 4. The compound of claim 3, ora pharmaceutically acceptable salt thereof, wherein R⁸ and R⁹ are eachhydrogen.
 5. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁵ and R⁶ are each C₁₋₆ alkyl.
 6. The compound ofclaim 5, or a pharmaceutically acceptable salt thereof, wherein R⁵ andR⁶ are each methyl.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ and R⁶ together with the carbon atomto which they are bound form a group selected from the group consistingof C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl and3-8 membered heterocycloalkenyl, each optionally substituted with 1, 2,3, 4 or 5 substituents selected from the group consisting of halogen,CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a),C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl and C₁₋₆ haloalkyl.
 8. The compound of claim 7, or apharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ togetherwith the carbon atom to which they are bound form C₃₋₈ cycloalkyloptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromthe group consisting of halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl. 9.The compound of claim 8, or a pharmaceutically acceptable salt thereof,wherein R⁵ and R⁶ together with the carbon atom to which they are boundform a group selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted with1, 2, 3, 4 or 5 substituents selected from the group consisting ofhalogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), NR^(b)R^(c),C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), S(O)R^(a), SO₂R^(a),SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl.
 10. The compound of claim9, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶together with the carbon atom to which they are bound form cyclobutyloptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromthe group consisting of halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c),S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl and C₁₋₆ haloalkyl. 11.The compound of claim 10, or a pharmaceutically acceptable salt thereof,wherein R⁵ and R⁶ together with the carbon atom to which they are boundform cyclobutyl optionally substituted with one or two halogens.
 12. Thecompound of claim 11, or a pharmaceutically acceptable salt thereof,wherein R⁵ and R⁶ together with the carbon atom to which they are boundform a group selected from the group consisting of cyclobutyl,3-fluorocyclobutyl and 3,3-difluorocyclobutyl. 13-18. (canceled)
 19. Thecompound of claim 1, wherein the compound is of Formula IV(e) or IV(f),or a pharmaceutically acceptable salt thereof:

wherein R^(m) and R^(n) are each independently selected from the groupconsisting of hydrogen, halogen and C₁₋₆ alkyl.
 20. The compound ofclaim 1, wherein the compound is of Formula V(e) or V(f), or apharmaceutically acceptable salt thereof:

wherein R^(m) and R^(n) are each independently selected from the groupconsisting of hydrogen, halogen and C₁₋₆ alkyl.
 21. The compound ofclaim 19, or a pharmaceutically acceptable salt thereof, wherein one ofR^(m) and R^(n) is hydrogen and the other is halogen.
 22. The compoundof claim 21, or a pharmaceutically acceptable salt thereof, wherein thehalogen and R⁷ are in a trans configuration with respect to one anotheron the cyclobutyl ring.
 23. The compound of claim 21, or apharmaceutically acceptable salt thereof, wherein the halogen and R⁷ arein a cis configuration with respect to one another on the cyclobutylring.
 24. The compound of claim 21, or a pharmaceutically acceptablesalt thereof, wherein one of R^(m) and R^(n) is hydrogen and the otheris fluorine.
 25. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is phenyl optionally substitutedwith 1, 2, 3, 4 or 5 substituents selected from the group consisting ofhalogen, CN, oxo, OR^(a), OC(O)R^(a), OC(O)OR^(a), OC(O)NR^(b)R^(c),NR^(b)R^(c), NR^(d)C(O)R^(a), NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c),NR^(d)C(O)C(O)NR^(b)R^(c), NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a),NR^(d)C(S)NR^(b)R^(c), NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a),NR^(d)SO₂R^(a), NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a),C(O)NR^(b)R^(c), C(S)R^(a), C(S)OR^(a), C(S)NR^(b)R^(c),C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a), SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl, and 5-10 memberedheteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁ aralkyl and 5-10 memberedheteroaryl groups is optionally substituted with 1, 2, 3, 4 or 5 R^(f)substituents.
 26. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is 5-10 membered heteroaryloptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromthe group consisting of halogen, CN, oxo, OR^(a), OC(O)R^(a),OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl, C₇₋₁₁aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀ aryl,C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.
 27. The compound ofclaim 26, or a pharmaceutically acceptable salt thereof, wherein R⁷ ispyridyl optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from the group consisting of halogen, CN, oxo, OR^(a),OC(O)R^(a), OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, 3-6 memberedheterocycloalkyl, 3-6 membered heterocycloalkenyl, phenyl, naphthyl,C₇₋₁₁ aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀aryl, C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.
 28. The compound ofclaim 27, or a pharmaceutically acceptable salt thereof, wherein R⁷ is2-pyridyl optionally substituted with 1, 2, 3, 4 or 5 substituentsselected from the group consisting of halogen, CN, oxo, OR^(a),OC(O)R^(a), OC(O)OR^(a), OC(O)NR^(b)R^(c), NR^(b)R^(c), NR^(d)C(O)R^(a),NR^(d)C(O)OR^(a), NR^(d)C(O)NR^(b)R^(c), NR^(d)C(O)C(O)NR^(b)R^(c),NR^(d)C(S)R^(a), NR^(d)C(S)OR^(a), NR^(d)C(S)NR^(b)R^(c),NR^(d)C(NR^(e))NR^(b)R^(c), NR^(d)S(O)R^(a), NR^(d)SO₂R^(a),NR^(d)SO₂NR^(b)R^(c), C(O)R^(a), C(O)OR^(a), C(O)NR^(b)R^(c), C(S)R^(a),C(S)OR^(a), C(S)NR^(b)R^(c), C(NR^(e))NR^(b)R^(c), SR^(a), S(O)R^(a),SO₂R^(a), SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkenyl, 3-6 memberedheterocycloalkyl, 3-6 membered heterocycloalkenyl, phenyl, naphthyl,C₇₋₁₁ aralkyl, and 5-10 membered heteroaryl, wherein each of the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl, C₆₋₁₀aryl, C₇₋₁₁ aralkyl and 5-10 membered heteroaryl groups is optionallysubstituted with 1, 2, 3, 4 or 5 R^(f) substituents.
 29. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein X is abond.
 30. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R² is phenyl optionally substituted with 1, 2, 3, 4 or5 substituents selected from the group consisting of halogen, CN,(CH₂)OR^(a), (CH₂)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 31. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is 5-10 membered heteroaryloptionally substituted with 1, 2, 3, 4 or 5 substituents selected fromthe group consisting of halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)N^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)S R^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 32. The compound of claim 31, or apharmaceutically acceptable salt thereof, wherein R² is selected fromthe group consisting of pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl,furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl,each optionally substituted with 1, 2, 3 or 4 substituents selected fromthe group consisting of halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 33. The compound of claim 32, or apharmaceutically acceptable salt thereof, wherein R² is selected fromthe group consisting of pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl,furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl,each optionally substituted with a substituent selected from the groupconsisting of (CH₂)_(n)C(O)OR^(a) and (CH₂)_(n)C(O)NR^(b)R^(c); andoptionally substituted with 1, 2 or 3 additional substituents selectedfrom the group consisting of halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S)OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8membered heterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and(CH₂)_(n)5-10 membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 34. The compound of claim 33, or apharmaceutically acceptable salt thereof, wherein R² is selected fromthe group consisting of furanyl, pyrrolyl, thiophenyl, thiazolyl,isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,imidazolyl, triazolyl and tetrazolyl, each optionally substituted with(CH₂)_(n)C(O)NR^(b)R^(c).
 35. The compound of claim 32, or apharmaceutically acceptable salt thereof, wherein R² is selected fromthe group consisting of pyridyl, pyrimidyl, pyrazyl, pyridazyl, triazyl,furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and tetrazolyl,each optionally substituted with (CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a)is C₁₋₆ alkyl or 3-8 membered heterocycloalkyl, each optionallysubstituted with 1, 2 or 3 additional substituents selected from thegroup consisting of halogen, CN, oxo, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(S)R^(a),(CH₂)_(n)NR^(d)C(S) OR^(a), (CH₂)_(n)NR^(d)C(S)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)NR^(d)S(O)R^(a),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a), (CH₂)_(n)C(S)NR^(b)R^(c),(CH₂)_(n)C(NR^(e))NR^(b)R^(c), (CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a),(CH₂)_(n)SO₂R^(a), (CH₂)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 36. The compound of claim 35, or apharmaceutically acceptable salt thereof, wherein R² is is selected fromthe group consisting of furanyl, pyrrolyl, thiophenyl, thiazolyl,isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,imidazolyl, triazolyl and tetrazolyl, each optionally substituted with(CH₂)_(n)NR^(d)C(O)R^(a), wherein R^(a) is selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ alkyl-OH and C₁₋₆ alkyl-NH₂, eachoptionally substituted with 1, 2 or 3 additional substituents selectedfrom the group consisting of halogen, CN, (CH₂)_(n)OR^(a),(CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a), (CH₂)_(n)OC(O)NR^(b)R^(c),(CH₂)_(n)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)R^(a),(CH₂)_(n)NR^(d)C(O)OR^(a), (CH₂)_(n)NR^(d)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)SO₂R^(a), (CH₂)_(n)NR^(d)SO₂NR^(b)R^(c),(CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a), (CH₂)_(n)C(O)NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl.
 37. The compound of claim 31, or a pharmaceuticallyacceptable salt thereof, wherein R² is selected from the groupconsisting of indolyl, indazolyl, benzimidazolyl, benzoxazolyl andbenzoisoxazolyl, each optionally substituted with 1, 2, 3 or 4substituents selected from the group consisting of halogen, CN, oxo,(CH₂)_(n)OR^(a), (CH₂)_(n)OC(O)R^(a), (CH₂)_(n)OC(O)OR^(a),(CH₂)_(n)OC(O)NR^(b)R^(c), (CH₂)_(n)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(O)R^(a), (CH₂)_(n)NR^(d)C(O)OR^(a),(CH₂)_(n)NR^(d)C(O)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(O)C(O)NR^(b)R^(c),(CH₂)_(n)NR^(d)C(S)R^(a), (CH₂)_(n)NR^(d)C(S)OR^(a),(CH₂)_(n)NR^(d)C(S)NR^(b)R^(c), (CH₂)_(n)NR^(d)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)NR^(d)S(O)R^(a), (CH₂)_(n)NR^(d)SO₂R^(a),(CH₂)_(n)NR^(d)SO₂NR^(b)R^(c), (CH₂)_(n)C(O)R^(a), (CH₂)_(n)C(O)OR^(a),(CH₂)_(n)C(O)NR^(b)R^(c), (CH₂)_(n)C(S)R^(a), (CH₂)_(n)C(S)OR^(a),(CH₂)_(n)C(S)NR^(b)R^(c), (CH₂)_(n)C(NR^(e))NR^(b)R^(c),(CH₂)_(n)SR^(a), (CH₂)_(n)S(O)R^(a), (CH₂)_(n)SO₂R^(a),(CH₂)_(n)SO₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl, wherein each of the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)3-8 memberedheterocycloalkyl, (CH₂)_(n)phenyl, (CH₂)_(n)naphthyl and (CH₂)_(n)5-10membered heteroaryl groups is optionally substituted with 1, 2, 3, 4 or5 R^(f) substituents.
 38. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹, at each occurrence, is selectedfrom the group consisting of hydrogen, halogen, CN, CF₃ and methyl. 39.The compound of claim 38, or a pharmaceutically acceptable salt thereof,wherein R¹, at each occurrence, is hydrogen.
 40. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R⁴ ishydrogen.
 41. A compound selected from the group consisting of,(6-bromo(2-pyridyl)) [2-(4-fluorophenyl)-2-methylpropyl]amine;[2-(4-fluorophenyl)-2-methylpropyl][6-(2-methylprop-1-enyl)(2-pyridyl)]amine;[6-(4-fluorophenyl)(2-pyridyl)][2-(4-fluorophenyl)-2-methylpropyl]amine;[4-(4-fluorophenyl)(2-pyridyl)][2-(4-fluorophenyl)-2-methylpropyl]amine;4-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)benzamide;3-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)benzamide;6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridine-3-carbonitrile;3-(6-{[2-(4-fluorophenyl)ethyl]amino}-3-pyridyl)benzamide;6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}pyridine-3-carboxamide;N-[(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}(3-pyridyl))methyl]methoxycarboxamide;tert-butyl2-[(5-bromo-2-pyridyl)amino]acetate;3-{6-[2-(4-fluorophenyl)acetylamino]-3-pyridyl}benzamide;1-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)ethane-1,2-diol;3-(6-{[(2S)-2-(4-fluorophenyl)propyl]amino}-3-pyridyl)benzamide;3-(6-{[(2R)-2-(4-fluorophenyl)propyl]amino}-3-pyridyl)benzamide;3-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)propane-1,2-diol;N-[2-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}(3-pyridyl))ethyl]methoxycarboxamide;[2-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}(3-pyridyl)ethyl](methylsulfonyl)amine;N-[2-(6-{[2-(4-fluorophenyl)-2-methylpropyl]amino}-3-pyridyl)ethyl]acetamide;2-{[2-(4-fluorophenyl)-2-methylpropyl]amino}quinoline-6-carboxamide;(4-phenyl(2-pyridyl))(phenylcyclobutyl)amine;(6-phenyl(2-pyridyl))(phenylcyclobutyl)amine;(5-phenyl(2-pyridyl))(phenylcyclobutyl)amine; and3-[5-fluoro-6-({[3-fluoro-1-(3-fluoro(2-pyridyl))cyclobutyl]methyl}amino)-3-pyridyl]benzamide;or a pharmaceutically acceptable salt thereof.
 42. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 43. The pharmaceutical composition of claim 42,wherein the pharmaceutical composition is formulated for oral,sublingual, subcutaneous, parenteral, intravenous, intranasal, topical,transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal,rectal, or intraocular administration.
 44. The pharmaceuticalcomposition of claim 43, wherein the pharmaceutical composition isformulated for oral administration.
 45. A method of treating a diseaseor condition selected from the group consisting of neuromusculardisorders, conditions of muscle wasting, muscular myopathies,rehabilitation-related deficits, peripheral vascular disease, peripheralarterial disease, frailty, muscle atrophy and fatigue, metabolicsyndrome, chronic fatigue syndrome, and obesity, comprisingadministering to an individual in need thereof an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 46. Amethod of treating a disease selected from the group consisting ofAmyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), andmyasthenia gravis, comprising administering to an individual in needthereof an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 47. A method of treating adisease selected from the group consisting of peripheral vasculardisease and peripheral arterial disease, comprising administering to anindividual in need thereof an effective amount of a compound of claim 1or a pharmaceutically acceptable salt thereof.
 48. The compound of claim20, or a pharmaceutically acceptable salt thereof, wherein one of R^(m)and R^(n) is hydrogen and the other is halogen.
 49. The compound ofclaim 48, or a pharmaceutically acceptable salt thereof, wherein thehalogen and R⁷ are in a trans configuration with respect to one anotheron the cyclobutyl ring.
 50. The compound of claim 48, or apharmaceutically acceptable salt thereof, wherein the halogen and R⁷ arein a cis configuration with respect to one another on the cyclobutylring.
 51. The compound of claim 48, or a pharmaceutically acceptablesalt thereof, wherein one of R^(m) and R^(n) is hydrogen and the otheris fluorine.
 52. A method of treating Chronic Obstructive PulmonaryDisease (COPD), comprising administering to an individual in needthereof an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 53. A method of treating heartfailure, comprising administering to an individual in need thereof aneffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof.